WO2023221721A1 - Shp2抑制剂及其用途 - Google Patents

Shp2抑制剂及其用途 Download PDF

Info

Publication number
WO2023221721A1
WO2023221721A1 PCT/CN2023/089203 CN2023089203W WO2023221721A1 WO 2023221721 A1 WO2023221721 A1 WO 2023221721A1 CN 2023089203 W CN2023089203 W CN 2023089203W WO 2023221721 A1 WO2023221721 A1 WO 2023221721A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
group
shp2 inhibitor
add
Prior art date
Application number
PCT/CN2023/089203
Other languages
English (en)
French (fr)
Inventor
李志文
刘明清
刘相军
Original Assignee
安徽中科拓苒药物科学研究有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 安徽中科拓苒药物科学研究有限公司 filed Critical 安徽中科拓苒药物科学研究有限公司
Publication of WO2023221721A1 publication Critical patent/WO2023221721A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention belongs to the field of medicinal chemistry, and specifically relates to a class of SHP2 inhibitors and their uses.
  • SHP2 is a non-receptor protein tyrosine phosphatase encoded by the gene PTPN11. It can catalyze the dephosphorylation of phosphorylated substrates (such as receptors, kinases and phospholipids, etc.), thereby regulating downstream signals. It is the current protein tyrosine phosphatase. It is the only confirmed proto-oncoprotein in the amino acid phosphatase (PTP) family. SHP2 usually forms a complex with growth factor receptor binding protein 2 (GRB2), GRB2-associated binding protein (GAB1), and signaling molecule protein (SOS), thereby activating the growth signaling pathway RAS-MAPK to promote oncogenic signaling.
  • GRB2 growth factor receptor binding protein 2
  • GRB1 GRB2-associated binding protein
  • SOS signaling molecule protein
  • Dysregulation of SHP2 can lead to the occurrence of a variety of diseases: mutations that activate PTPN11 usually disrupt the N-SH2/PTP domain interaction in the closed conformation, tending SHP2 to the open conformation, and increase the activation of downstream RAS/MAPK; and this signaling Activation will lead to the occurrence of various hematological malignancies. This proves that PTPN11 is a true oncogene.
  • SHP2 is widely expressed in various cells of the body and participates in important cell life activities including cell proliferation, activation, migration, differentiation, etc.
  • SHP2-mediated activation of RAS-MAPK signaling and its negative regulatory effect on JAK-STAT signaling make SHP2 an important participant in oncogenic or tumor suppressor signaling pathways.
  • Gain-of-function SHP2 mutations result in increased phosphatase activity leading to Noonan syndrome, as well as various forms of leukemia (e.g., juvenile myelomonocytic leukemia, acute myelogenous leukemia, myelodysplastic syndromes, acute lymphoblastic leukemia) and Various solid tumors (eg, lung adenocarcinoma, colon cancer, neuroblastoma, glioblastoma, melanoma, hepatocellular carcinoma, and prostate cancer). Therefore, SHP2 is a potential therapeutic target for various cancers, and the development of SHP2 inhibitors has attracted more and more attention. Therefore, discovering and searching for SHP2 inhibitors with good druggability has become a popular target in industry and academia. Currently, no SHP2 inhibitor has been approved for marketing, so there is still a clinical need to explore highly active SHP2 inhibitors.
  • leukemia e.g., juvenile myelomonocytic leukemia,
  • One object of the present invention is to provide a new class of SHP2 enzyme inhibitors that can be used to treat cancer and other diseases.
  • the present invention relates to a compound as an inhibitor of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), or a pharmaceutically acceptable salt, isomer, solvate, chelate, Polymorphs, acids, esters, metabolites or prodrugs of the compound represented by Formula I:
  • A is an aryl or heteroaryl group, preferably selected from phenyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
  • B is a nitrogen-containing unsaturated monocyclic or bicyclic ring, preferably selected from pyrazine (for example ), pyrazolopyrimidinones (e.g. ), and pyrazolopyrazines (e.g. );
  • n are each independently 0, 1 or 2;
  • R 1 and R 1 ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R1 and R1 ' together form benzospirocyclopentyl, where the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 to 3 R6 ;
  • R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group
  • R 3 is selected from H, hydroxyl, and halogen
  • R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, C1-6 hydroxyalkyl, 5 or 6
  • R 5 is each independently selected from C1-C4 alkyl, C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl;
  • Each R 6 is independently selected from halogen, amino and C1-6 alkoxy.
  • R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ; more preferably, R 1 and R 1 ' together form When R6 is present, R6 is selected from halogen and C1-6 alkoxy. Additionally preferably, R 2 and R 2 ' are each H; R 3 is H; and R 6 are each independently selected from halogen and C1-6 alkoxy.
  • R 1 and R 1 ' are each independently selected from H, C1-3 alkyl, amino, C1-3 aminoalkyl, hydroxyl, C1-3 hydroxyalkyl, C1-3 alkyl Amide, and oxo, or R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
  • R 2 and R 2 ' are each H, or linked together to form ethylene;
  • R 3 is selected from H, hydroxyl, and fluorine;
  • R 4 is each independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, C3-5 cycloalkyl, C3-5 cycloalkyl C1-3 alkyl, C1-3 hydroxyalkyl, tetrahydrofuryl, tetrahydropyranyl, morpholin-4ylethyl, and benzene optionally substituted by 1 to 3 R6 base, pyri
  • the invention relates to a compound that is a SHP2 inhibitor, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or pro- Body medicine, the compound is shown in Formula Ia:
  • A, n, R 1 and R 1 ', R 2 and R 2 ', R 3 , R 4 and R 5 are as defined above.
  • A is selected from phenyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
  • n 1 or 2;
  • R 1 and R 1 ' are each independently selected from C1-6 alkyl, C1-6 aminoalkyl, and hydroxyl, or R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted with amino and Phenyl is optionally substituted by 1 R 6 ;
  • R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group (preferably ethylene);
  • R 3 is H
  • R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, phenyl, and 5 or 6 membered heterocycle Alkyl (preferably tetrahydrofuryl);
  • R 5 is C1-C4 alkyl (preferably methyl);
  • R 6 is selected from halogen and C1-6 alkoxy.
  • A is imidazopyridyl, preferably imidazo[4,5-b]pyridyl, more preferably selected from
  • R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by halogen or C1-6 alkoxy, more preferably by fluorine or methyl. Oxygen substitution.
  • the invention relates to a compound that is a SHP2 inhibitor, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or Prodrug, the compound is represented by formula Ib:
  • R 1 and R 1 ', R 2 and R 2 ', R 3 and R 4 are as defined above.
  • A is selected from phenyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
  • n 1 or 2;
  • R 1 and R 1 ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
  • R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group (preferably ethylene);
  • R 3 is selected from H, hydroxyl, and halogen
  • R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 hydroxyalkyl, 5- or 6-membered heterocycloalkyl (preferably tetrahydrofuryl or tetrahydrofuranyl) Pyranyl), 5- or 6-membered heterocycloalkyl C1-6 alkyl (preferably morpholin-4 ethyl), and phenyl, pyridyl, pyrimidinyl, or isoxazolyl optionally substituted by 1 to 3 R 6 ;
  • Each R 6 is independently selected from halogen and C1-6 alkoxy.
  • A is imidazopyridyl, preferably imidazo[4,5-b]pyridyl, more preferably
  • R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by C1-6 alkoxy, more preferably substituted by methoxy.
  • the invention relates to a compound that is a SHP2 inhibitor, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or Prodrug, the compound is represented by formula Ic:
  • R 1 and R 1 ', R 2 and R 2 ', R 3 and R 5 are as defined above.
  • A is selected from imidazopyridyl (e.g. imidazo[4,5-b]pyridyl, in particular ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
  • n 1 or 2;
  • R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
  • R 2 and R 2 ' are each H;
  • R 3 is H
  • R 4 is each independently selected from C1-6 haloalkyl, C3-6 cycloalkyl, and phenyl optionally substituted by 1 to 3 R 6 , and pyridyl;
  • R 5 is selected from C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl
  • Each R 6 is independently selected from halogen, amino and C1-6 alkoxy.
  • A is imidazopyridyl, preferably imidazo[4,5-b]pyridyl, more preferably
  • R 5 is C1-C4 hydroxyalkyl, more preferably hydroxymethyl.
  • the application also provides compounds of Formula I, Ia, Ib or Ic or pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, esters, metabolites thereof or a pharmaceutical composition of a prodrug, and a pharmaceutically acceptable diluent or carrier, and optionally other active pharmaceutical ingredients.
  • the application also relates to a compound of Formula I, Ia, Ib or Ic, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or Methods and uses of prodrugs for inhibiting SHP2 activity.
  • the application also relates to a compound of formula I, Ia, Ib or Ic or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite thereof or prodrugs, methods and uses for treating, preventing or alleviating diseases mediated by SHP2.
  • the disease is selected from cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or ocular disease.
  • the disease is selected from cancer, in particular from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors , lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
  • cancer in particular from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors , lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
  • the application also relates to a compound of Formula I, Ia, Ib or Ic, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or Use of prodrugs in the preparation of medicaments for treating, preventing or alleviating diseases mediated by SHP2.
  • the disease is selected from cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or ocular disease.
  • the disease is selected from cancer, in particular from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors , lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
  • cancer in particular from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors , lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
  • the present invention adopts conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology within the technical scope of the art.
  • mass spectrometry NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology
  • specific definitions are provided, the nomenclature and laboratory procedures and techniques chemically relevant to the analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry described herein are known to those skilled in the art.
  • the foregoing techniques and steps may be carried out by conventional methods that are well known in the art and described in various general and more specific documents, which are cited and discussed in this specification.
  • alkyl refers to an aliphatic hydrocarbon group, which may be branched or straight chain. Depending on the structure, an alkyl group can So it is a monovalent group or a bivalent group (i.e. alkylene group).
  • the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a “lower alkyl group” having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms.
  • Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.
  • alkyl includes all possible configurations and conformations of the alkyl group.
  • the "propyl” mentioned herein includes n-propyl and isopropyl
  • the "butyl” includes n-butyl. base, isobutyl and tert-butyl
  • "pentyl” includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and pentyl-3-yl, etc.
  • alkoxy refers to -O-alkyl, where alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.
  • alkoxyalkyl means an alkyl group as defined herein substituted by an alkoxy group as defined herein.
  • cycloalkyl refers to a monocyclic or polycyclic group containing only carbon and hydrogen. Cycloalkyl groups include groups having 3 to 12 ring atoms. Depending on the structure, a cycloalkyl group can be a monovalent group or a bivalent group (eg, cycloalkylene). In the present invention, the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, and more preferably a “lower cycloalkyl group” having 3 to 6 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantane base.
  • alkyl(cycloalkyl) or "cycloalkylalkyl” means an alkyl group as defined herein substituted by a cycloalkyl group as defined herein.
  • Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
  • aryl refers to a planar ring having a delocalized pi electron system and containing 4n+2 pi electrons, where n is an integer.
  • Aryl rings may be composed of five, six, seven, eight, nine, or more than nine atoms.
  • Aryl groups may be optionally substituted.
  • aryl includes carbocyclic aryl (eg, phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaryl”) groups (eg, pyridine).
  • the term includes monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.
  • aryl means an aryl ring in which each ring-constituting atom is a carbon atom.
  • Aryl rings can be composed of five, six, seven, eight, nine, or more than nine atoms.
  • Aryl groups may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl.
  • an aryl group can be a monovalent group or a bivalent group (i.e., arylene group).
  • aryloxy refers to -O-aryl, where aryl is as defined herein.
  • heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the N-containing “heteroaryl” part refers to an aromatic group in which at least one skeleton atom in the ring is a nitrogen atom.
  • a heteroaryl group can be a monovalent group or a bivalent group (i.e., a heteroarylene group).
  • heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazole base, isothiazolyl, pyrrolyl, quinolyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindole Indolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl , naphthyridinyl and furopyr
  • alkyl(aryl) or “aralkyl” means an alkyl group as defined herein substituted by an aryl group as defined herein.
  • No Limiting alkyl (aryl) groups include benzyl, phenethyl, and the like.
  • alkyl(heteroaryl) or “heteroarylalkyl” means an alkyl group as defined herein substituted by a heteroaryl group as defined herein.
  • heteroalkyl as used herein means an alkyl group as defined herein in which one or more of the backbone chain atoms are heteroatoms, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof.
  • the heteroatom(s) may be located anywhere within the heteroalkyl group or at the position where the heteroalkyl group is attached to the rest of the molecule.
  • heterocycloalkyl refers to a non-aromatic ring in which one or more of the ring-constituting atoms is a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur.
  • Heterocycloalkyl rings may be monocyclic or polycyclic rings composed of three, four, five, six, seven, eight, nine or more than nine atoms. Heterocycloalkyl rings may be optionally substituted.
  • heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimines, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4- Oxathiane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, apeloline Bituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, Te
  • alkyl(heterocycloalkyl) or “heterocycloalkylalkyl” means an alkyl group as defined herein substituted by a heterocycloalkyl group as defined herein.
  • alkoxy(heterocycloalkyl) or “heterocycloalkylalkoxy” means an alkoxy group as defined herein substituted by a heterocycloalkyl group as defined herein.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • haloalkyl examples include alkyl, alkoxy or heteroalkyl structures in which at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same as or different from each other.
  • oxadiazolyl refers to the isomeric forms of oxadiazolyl including 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4-oxadiazolyl. Azolyl.
  • oxazolyl refers to oxazolyl groups including 1,2-oxazolyl (isoxazolyl), 1,3-oxazolyl and other isomeric forms.
  • hydroxy refers to the -OH group.
  • cyano refers to the -CN group.
  • ester group refers to a chemical moiety having the formula -COOR, wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and heterocyclyl (attached through a ring carbon).
  • amino refers to the -NH group .
  • aminoacyl refers to the -CO- NH2 group.
  • alkylaminoacyl refers to the group -CO-NH-R, where R is alkyl as defined herein.
  • amide or “amido” refers to -NR-CO-R', where R and R' are each independently hydrogen or alkyl.
  • alkylamino refers to an amino substituent further substituted by one or two alkyl groups, and specifically refers to the group -NRR', wherein R and R' are each independently selected from hydrogen or lower alkyl, provided that - NRR' is not -NH 2 .
  • Alkylamino includes groups of compounds in which the -NH2 nitrogen is bonded to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like.
  • Dialkylamino includes groups in which the nitrogen of -NH2 is bonded to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.
  • arylamino and diarylamino refer to amino substituents further substituted by one or two aryl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen, Lower alkyl, or aryl, wherein N is connected to at least one or two aryl groups respectively.
  • cycloalkylamino refers to an amino substituent further substituted by one or two cycloalkyl groups as defined herein.
  • heteroalkylamino refers to an amino substituent further substituted with one or two heteroalkyl groups as defined herein.
  • aralkyl amino herein refers to the group -NRR' wherein R is lower aralkyl and R' is hydrogen, lower alkyl, aryl or lower aralkyl.
  • heteroarylamino refers to an amino substituent further substituted by one or two heteroaryl groups as defined herein.
  • heterocycloalkylamino means an amino group, as defined herein, substituted by a heterocycloalkyl group, as defined herein.
  • alkylaminoalkyl means an alkyl group, as defined herein, substituted with an alkylamino group, as defined herein.
  • aminoalkyl refers to an alkyl substituent further substituted with one or more amino groups.
  • aminoalkoxy refers to an alkoxy substituent further substituted with one or more amino groups.
  • hydroxyalkyl or "hydroxyalkyl” refers to an alkyl substituent further substituted by one or more hydroxyl groups.
  • cyanoalkyl refers to an alkyl substituent further substituted with one or more cyano groups.
  • acyl refers to the monovalent atomic group remaining after removing the hydroxyl group from an organic or inorganic oxygen-containing acid.
  • the general formula is R-M(O)-, where M is usually C.
  • alkanoyl or “alkylcarbonyl” refers to a carbonyl group further substituted by an alkyl group.
  • Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, caproyl, etc.
  • arylcarbonyl means a carbonyl group as defined herein substituted by an aryl group as defined herein.
  • alkoxycarbonyl refers to a carbonyl group further substituted by an alkoxy group.
  • heterocycloalkylcarbonyl refers to a carbonyl group further substituted by a heterocycloalkyl group.
  • alkylaminocarbonyl cycloalkylaminocarbonyl
  • arylaminocarbonyl aralkylaminocarbonyl
  • heteroarylaminocarbonyl respectively refer to a carbonyl group as defined herein.
  • alkylcarbonylalkyl or “alkanoylalkyl” refers to an alkyl group further substituted by an alkylcarbonyl group.
  • alkylcarbonylalkoxy or “alkanoylalkoxy” refers to an alkoxy group further substituted by an alkylcarbonyl group.
  • heterocycloalkylcarbonylalkyl refers to an alkyl group further substituted by a heterocycloalkylcarbonyl group.
  • mercapto refers to the -SH group.
  • alkylthio means a mercapto group, as defined herein, substituted by an alkyl group, as defined herein.
  • alkylaminosulfone means a sulfone group, as defined herein, substituted with an alkylamino group, as defined herein.
  • quaternary ammonium refers to -N + RR'R", where R, R' and R" are each independently selected from alkyl groups having 1 to 8 carbon atoms.
  • optional means that one or more of the events described below may or may not occur, and includes both events that occur and events that do not occur.
  • optionally substituted or “substituted” means that the mentioned group may be substituted by one or more additional groups each and independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroaryl Alkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc.
  • the amino protecting group is preferably selected from pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenemethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trifluoroacetyl, and the like.
  • pharmaceutically acceptable salt refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesirable toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the free acid or free base form of the purified compound with a suitable base or acid, respectively.
  • Solvate or “solvate” refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in a crystalline solid state, thus forming solvates. If the solvent is water, the solvate formed is a hydrate; if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with one molecule of the substance, where the water maintains its molecular state as H2O .
  • a “metabolite” of a compound disclosed herein is a derivative of the compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolism refers to the sum of the processes by which a specific substance is changed by an organism (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Therefore, enzymes can produce specific structural changes into compounds.
  • cytochrome P450 catalyzes various oxidation and reduction reactions
  • diphosphate glucuryltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups.
  • Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are known in the art.
  • the metabolites of the compounds are formed by oxidation processes and correspond to the corresponding hydroxyl-containing compounds.
  • the compound is metabolized to a pharmaceutically active metabolite.
  • the term "modulate” means interacting directly or indirectly with a target to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.
  • prodrug refers to a derivative that may not be pharmacologically active but, in some cases, may be administered orally or parenterally and is thereafter metabolized in the body to form a pharmacologically active drug.
  • Active compounds of the invention include: esters, carbonates, half-esters, phosphates, nitroesters, sulfates, sulfoxides, amides, carbamates, nitrogen-containing compounds, phosphoramides, glycosides, ethers, acetals Aldehydes and ketals, etc.
  • an “effective amount” refers to an amount of a drug or pharmaceutical preparation that will elicit a biological or medical response in a tissue, system, animal, or human being studied, for example, by a researcher or physician.
  • therapeutically effective amount refers to any amount that results in improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduction in the rate of progression of the disease or disorder, as compared to a corresponding subject who does not receive such amount. Also included within the term are amounts effective to enhance normal physiological functions.
  • treating refers to alleviating at least one symptom of a disease, disorder or condition.
  • the term includes administration and/or application to a subject of one or more compounds described herein to provide management or treatment of a condition.
  • Treatment for the purposes of this disclosure may, but need not, provide a cure; rather, “treatment” may be a form of management of the condition.
  • treating includes partial or complete destruction of the harmful proliferating cells with minimal destructive effect on normal cells. The required mechanism for dealing with harmful rapidly proliferating cells, including cancer cells, at the cellular level is apoptosis.
  • prevention includes co-preventing or slowing the onset of the development of clinically significant disease or preventing or slowing the onset of a preclinically significant stage of disease in an at-risk individual. This includes preventive treatment of individuals at risk of developing the disease.
  • subject or “patient” includes an organism capable of suffering from a condition or condition associated with reduced or insufficient programmed cell death (apoptosis) or otherwise deriving from administration of a compound of the invention.
  • beneficial organisms such as humans and non-human animals.
  • Preferred humans include those suffering from, or prone to suffering from, as described herein or related conditions in human patients.
  • non-human animals includes vertebrates such as mammals such as non-human primates, sheep, cattle, dogs, cats and rodents such as mice, as well as non-mammals such as chickens, amphibians, reptiles, etc. .
  • the GI 50 used herein refers to the drug concentration required to inhibit the growth of 50% of cells, that is, the drug concentration at which the growth of 50% of cells (such as cancer cells) is inhibited or controlled.
  • IC50 refers to the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximal effect in an assay measuring the effect.
  • EC50 refers to the dose, concentration, or amount of a test compound that elicits a dose-dependent response of 50% of the maximal expression of a specific response induced, stimulated, or potentiated by a particular test compound.
  • the present invention relates to a SHP2 inhibitor, which includes a compound as described in formula I, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite thereof or prodrugs:
  • A is an aryl or heteroaryl group, preferably selected from phenyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
  • B is a nitrogen-containing unsaturated monocyclic or bicyclic ring, preferably selected from pyrazine (for example ), pyrazolopyrimidinones (e.g. ), and pyrazolopyrazines (e.g. );
  • n are each independently 0, 1 or 2;
  • R 1 and R 1 ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R1 and R1 ' together form benzospirocyclopentyl, where the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 to 3 R6 ;
  • R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group
  • R 3 is selected from H, hydroxyl, and halogen
  • R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, C1-6 hydroxyalkyl, 5 or 6
  • R 5 is each independently selected from C1-C4 alkyl, C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl;
  • Each R 6 is independently selected from halogen, amino and C1-6 alkoxy.
  • R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ; more preferably R 1 and R 1 ' together form When R6 is present, R6 is selected from halogen (eg, fluorine) and C1-6 alkoxy (eg, methoxy).
  • halogen eg, fluorine
  • C1-6 alkoxy eg, methoxy
  • R 1 and R 1 ' are each independently selected from H, C1-3 alkyl, amino, C1-3 aminoalkyl, hydroxyl, C1-3 hydroxyalkyl, C1-3 alkyl Amide, and oxo, or R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
  • R 2 and R 2 ' are each H, or linked together to form ethylene;
  • R 3 is selected from H, hydroxyl, and fluorine;
  • R 4 is each independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, C3-5 cycloalkyl, C3-5 cycloalkyl C1-3 alkyl, C1-3 hydroxyalkyl, tetrahydrofuryl, tetrahydropyranyl, morpholin-4ylethyl, and benzene optionally substituted by 1 to 3 R6 base, pyri
  • R 2 and R 2 ' are each H; R 3 is H; and R 6 are each independently selected from halogen and C1-6 alkoxy.
  • the present invention relates to a SHP2 inhibitor, which includes a compound represented by formula Ia, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, Esters, metabolites or prodrugs:
  • A, n, R 1 and R 1 ', R 2 and R 2 ', R 3 , R 4 and R 5 are as defined above.
  • A is selected from phenyl, and imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
  • n 1 or 2;
  • R 1 and R 1 ' are each independently selected from C1-6 alkyl, C1-6 aminoalkyl, and hydroxyl, or R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted with amino and Phenyl is optionally substituted by 1 R 6 ;
  • R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group (preferably ethylene);
  • R 3 is H
  • R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, phenyl, and 5 or 6 membered heterocycle Alkyl (preferably tetrahydrofuryl);
  • R 5 is C1-C4 alkyl (preferably methyl);
  • R 6 is selected from halogen and C1-6 alkoxy.
  • A is imidazopyridyl, in particular imidazo[4,5-b]pyridyl, more particularly selected from Additionally preferably, R 1 and R 1 ' together form benzospirocyclopentyl, wherein pentyl is substituted by amino and phenyl optionally by halogen (eg fluorine) or C1-6 alkoxy (eg methoxy) replace.
  • halogen eg fluorine
  • C1-6 alkoxy eg methoxy
  • the present invention relates to compounds represented by Formula I or Formula Ia listed in Table 1 below, or their pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, Esters, metabolites or prodrugs.
  • the present invention relates to a SHP2 inhibitor, which includes a compound represented by formula Ib, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, Acids, esters, metabolites or prodrugs:
  • R 1 and R 1 ', R 2 and R 2 ', R 3 and R 4 are as defined above.
  • A is selected from phenyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, especially ), and oxadiazolyl (e.g. [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and isoxazolyl (e.g. isoxazol-3-yl, especially );
  • n 1 or 2;
  • R 1 and R 1 ' are each independently selected from H, C1-6 alkyl, amino, C1-6 aminoalkyl, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkylamido, and oxo, or R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
  • R 2 and R 2 ' are each H, or are joined together to form a C2-4 alkylene group (preferably ethylene);
  • R 3 is selected from H, hydroxyl, and halogen
  • R 4 is each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 hydroxyalkyl, 5- or 6-membered heterocycloalkyl (preferably tetrahydrofuryl or tetrahydrofuranyl) Pyranyl), 5- or 6-membered heterocycloalkyl C1-6 alkyl (preferably morpholin-4-ethyl), and phenyl, pyridyl, pyrimidinyl optionally substituted by 1 to 3 R6 , or isoxazolyl;
  • Each R 6 is independently selected from halogen and C1-6 alkoxy.
  • A is imidazopyridyl, especially imidazo[4,5-b]pyridyl, more particularly Further preferably, R 1 and R 1 ' together form benzospirocyclopentyl, wherein the pentyl group is substituted by amino and the phenyl group is optionally substituted by C1-6 alkoxy (eg methoxy).
  • the present invention relates to the compounds represented by Formula I or Formula Ib listed in Table 2 below, or their pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, Esters, metabolites or prodrugs.
  • the present invention relates to a SHP2 inhibitor, which includes a compound represented by formula Ic, or a pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, etc. , ester, metabolite or prodrug:
  • R 1 and R 1 ', R 2 and R 2 ', R 3 and R 5 are as defined above.
  • A is selected from imidazopyridyl (e.g. imidazo[4,5-b]pyridyl, in particular ), oxadiazolyl (such as [1,2,4]oxadiazol-3-yl, especially ), oxazolyl and Isoxazolyl (e.g. isoxazol-3-yl, especially );
  • n 1 or 2;
  • R 1 and R 1 ' together form benzospirocyclopentyl, in which the pentyl group is substituted by amino and the phenyl group is optionally substituted by 1 R 6 ;
  • R 2 and R 2 ' are each H;
  • R 3 is H
  • R 4 is each independently selected from C1-6 haloalkyl, C3-6 cycloalkyl, and phenyl optionally substituted by 1 to 3 R 6 , and pyridyl;
  • R 5 is selected from C1-C4 hydroxyalkyl and C1-C4 alkoxycarbonyl
  • Each R 6 is independently selected from halogen, amino and C1-6 alkoxy.
  • A is imidazopyridyl, especially imidazo[4,5-b]pyridyl, more particularly Also preferably, R 5 is C1-C4 hydroxyalkyl, especially hydroxymethyl.
  • the present invention relates to the compounds represented by Formula I or Formula Ic listed in Table 3 below, or their pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, Esters, metabolites or prodrugs.
  • a compound described herein is administered to an organism in need thereof and is metabolized in the body to produce metabolites that are then used to produce the desired effect, including the desired therapeutic effect.
  • compositions described herein can be prepared and/or used as pharmaceutically acceptable salts.
  • Types of pharmaceutically acceptable salts include, but are not limited to: (1) Acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reaction with organic acids such as acetic acid, propionic acid, caproic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, lemon Acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethane sulfonate Acid, 1,2-ethanedisulfonic acid, 2-hydroxy
  • the corresponding counterions of pharmaceutically acceptable salts can be analyzed and identified using a variety of methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectrometry, mass spectrometry, or any thereof. combination.
  • the salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, solvent evaporation, or in the case of aqueous solutions, lyophilization.
  • Screening and characterization of pharmaceutically acceptable salts, polymorphs and/or solvates can be accomplished using a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, microscopic methods, elemental analysis.
  • Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid states).
  • Various microscopy techniques include, but are not limited to, IR microscopy and Raman microscopy.
  • the compound of formula I, Ia, Ib or Ic of the present invention or its pharmaceutically acceptable salt, isomer, solvate, chelate, polymorph, acid, ester, metabolite or prodrug, can Inhibit SHP2 activity, thereby achieving the purpose of treating, preventing or alleviating diseases mediated by SHP2.
  • SHP2 activity thereby achieving the purpose of treating, preventing or alleviating diseases mediated by SHP2.
  • this application protects compounds of formula I, Ia, Ib or Ic or pharmaceutically acceptable salts, isomers, solvates, chelates, polymorphs, acids, esters, metabolites or precursors thereof Use of a medicament in the preparation of a medicament for inhibiting SHP2 activity, or treating, preventing or alleviating diseases mediated by SHP2.
  • the disease is selected from cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or ocular disease.
  • the disease is selected from cancer, in particular from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors, lung cancer , colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
  • cancer in particular from juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumors, lung cancer , colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
  • a medicament comprising a compound of the present invention may be administered to a patient by at least one of injection, oral administration, inhalation, rectal and transdermal administration.
  • the amount of a given drug will depend on factors such as the specific dosage regimen, the type and severity of the disease or condition, and the uniqueness of the subject or host in need of treatment (e.g., body weight). ), however, the dosage to be administered may be routinely determined by methods known in the art, depending upon the particular surrounding circumstances, including, for example, the particular drug being employed, the route of administration, the condition being treated, and the subject or host being treated.
  • the dosage administered will typically be in the range of 0.02-5000 mg/day, for example about 1-1500 mg/day.
  • the required dose may conveniently be presented as one dose, or as divided doses administered simultaneously (or within a short period of time) or at appropriate intervals, for example two, three, four or more divided doses per day.
  • the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.
  • the reactions can be used sequentially to provide the compounds described herein; or they can be used to synthesize fragments that are added subsequently by methods described herein and/or methods known in the art.
  • provided herein are methods of making the tyrosine kinase inhibitor compounds described herein and methods of using them.
  • the compounds described herein can be synthesized using the following synthetic scheme. Compounds can be synthesized using methods similar to those described below, using appropriate alternative starting materials.
  • reaction product can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and other methods. These products can be characterized using conventional methods, including physical constants and spectral data.
  • PE petroleum ether
  • NMO N-methylmorpholine N-oxide
  • Ar Argon gas
  • IM5-2 (0.7g, 2.11mmol) was added to a 100mL single-neck flask, TFA (5.0mL) was added, iron powder (0.6g) was added, and the reaction was stirred for 3 hours.
  • LCMS detection showed that the raw materials were completely consumed. After adsorbing and removing the iron powder with a magnetic rod, the temperature was raised to reflux and the reaction was carried out for 10 hours. LCMS monitoring showed that the reaction was complete. Concentrate under reduced pressure to remove the solvent, dilute the residue with EA, neutralize the reaction solution with saturated sodium bicarbonate solution, separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter the concentrated target compound, and proceed to the next reaction without purification.
  • Dissolve compound IM16-2 (900mg, 3.3mmol) and sodium hydroxide (0.53g, 13.2mmol) in tetrahydrofuran (5mL) at room temperature, raise the temperature to 80-90°C and stir for 12-16 hours.
  • LCMS monitoring shows the reaction. completely. Lower the temperature, add water to it, extract the reaction solution twice with EA, wash the organic phase twice with water, dry with anhydrous sodium sulfate for 30 minutes, filter and concentrate to obtain 0.7g of the target substance.
  • the synthesis method of reference compound 2-1 was obtained through the synthesis of intermediates IM16 and IM13, with a mass spectrum [M+H] of 587.2.
  • reaction solution Slowly add the reaction solution to about 100 mL of saturated ammonium chloride solution, separate the layers, wash the organic phase twice with water and once with saturated brine, dry over anhydrous sodium sulfate, filter, wash the filter cake with EA, and concentrate the filtrate to dryness under vacuum 2.59g of product was obtained, yield: 80%. [M+H] +232 .
  • reaction solution Slowly add the reaction solution to about 100 mL of saturated ammonium chloride solution, separate the layers, wash the organic phase twice with water and once with saturated brine, dry over anhydrous sodium sulfate, filter, wash the filter cake with EA, and concentrate the filtrate to dryness under vacuum 2.59g of product was obtained, yield: 80%. [M+H] +232 .
  • the synthesis method of reference compound 1-1 is obtained through the synthesis of intermediates IM15 and IM18, [M+H]635.
  • the catalytic activity of SHP2 was determined using the end-point fluorescent enzymatic method with DiFMUP as the alternative substrate to determine the IC 50 value of the compound. Dephosphorization reactions were performed on black, 384-well light polystyrene plates. The total reaction volume was set to 24 ⁇ L/well. In order to keep the concentration of DMSO at a low level, compounds were diluted 4-fold with DMSO starting from 10 mM, for a total of 8 concentrations.
  • reaction buffer 60mM HEPES pH 7.2, 75mM NaCl, 75mM KCl, 1mM EDTA, 0.02% BSA, 5mM DTT
  • 0.5 nM SHP2 purchased from Signalchem, USA, p38-20G-10 was pre-incubated with 1 ⁇ M p-IRS1 peptide (Gill Biochemical, 86703) for 5 to 10 minutes to activate the enzyme, and then different concentrations of compound solutions or DMSO were added as a control.
  • the present invention provides a SHP2 inhibitor compound that can be used to inhibit SHP2 activity and/or treat, prevent or alleviate diseases mediated by SHP2 in a subject. Therefore, it can be made into corresponding drugs and suitable for industrial applications.

Abstract

一种SHP2抑制剂，其包括式(I)的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物。本发明还涉及包括该SHP2抑制剂的药物组合物、以及使用该SHP2抑制剂在抑制SHP2活性、或者治疗、预防或缓和由SHP2介导的疾病中的用途。

Description

SHP2抑制剂及其用途 技术领域
本发明属于药物化学领域，具体地，涉及一类SHP2抑制剂及其用途。
背景技术
SHP2是由基因PTPN11编码的一种非受体型蛋白酪氨酸磷酸酶，可以催化磷酸化的底物(如受体、激酶和磷脂等)去磷酸化，从而调控下游信号，是目前蛋白质酪氨酸磷酸酶(PTP)家族中唯一被证实的原癌蛋白。SHP2通常与生长因子受体结合蛋白2(GRB2)、GRB2相关结合蛋白(GAB1)以及信号分子蛋白(SOS)形成复合物，从而激活生长信号通路RAS-MAPK，以促进致癌信号传导。SHP2调节异常会导致多种疾病的发生：激活PTPN11的突变通常会破坏封闭构象的N-SH2/PTP域间相互作用，使SHP2倾向于开放构象，并增加下游RAS/MAPK的激活；而该信号的激活将导致多种血液***恶性肿瘤的发生。这证明了PTPN11是真正的致癌基因。作为多种细胞因子、生长因子以及其它胞外刺激因素的胞内响应信号分子，SHP2在机体的各种细胞中广泛表达，参与包括细胞增殖、活化、迁移、分化等重要的细胞生命活动。SHP2介导的RAS-MAPK信号激活及其对JAK-STAT信号的负调控作用使得SHP2成为致癌或抑癌信号通路的重要参与者。
功能获得性SHP2突变导致了增加的磷酸酶活性导致的Noonan综合征，以及多种形式的白血病(例如，青少年髓单核细胞白血病、急性骨髓性白血病、骨髓增生异常综合征、急性淋巴白血病)和多种实体瘤(例如，肺腺癌、结肠癌、成神经细胞瘤、成胶质细胞瘤、黑素瘤、肝细胞癌和***癌)。因此，SHP2是多种癌症的潜在的治疗靶点，SHP2抑制剂的开发吸引越来越多的关注。因此，发现和寻找具有较好成药性的SHP2抑制剂成为工业界和学术界的热门靶点。目前尚无SHP2抑制剂获批上市，因此探索高活性的SHP2抑制剂依然有临床需求。
发明内容
本发明的一个目的在于提供一类新型的SHP2酶抑制剂，可用于治疗癌症等疾病。
一方面，本发明涉及一种作为含Src同源区2蛋白质酪氨酸磷酸酶2(SHP2)抑制剂的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物，所述化合物如式I所示：
其中，
A为芳基或杂芳基，优选地选自苯基、咪唑并吡啶基(例如咪唑并[4,5-b]吡啶基，特别是)、噁二唑基(例如[1,2,4]噁二唑-3-基，特别是)、噁唑基和异噁唑基(例如异噁唑-3-基，特别是)；
B为含氮不饱和单环或双环，优选地选自吡嗪(例如)、吡唑并嘧啶酮(例如)、和吡唑并吡嗪(例如)；
m和n各自独立地为0、1或2；
R1和R1'各自独立地选自H、C1-6烷基、氨基、C1-6氨基烷基、羟基、C1-6羟基烷基、C1-6烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1至3个R6取代；
R2和R2'各自为H，或连接在一起形成C2-4亚烷基；
R3选自H、羟基、和卤素；
R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C3-6环烷基C1-6烷基、C1-6羟基烷基、5或6元杂环烷基、5或6元杂环烷基C1-6烷基、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；
R5各自独立地选自C1-C4烷基、C1-C4羟基烷基和C1-C4烷氧基羰基；
R6各自独立地选自卤素、氨基和C1-6烷氧基。
优选地，R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；更优选地，R1和R1'一起形成 当存在R6时，R6选自卤素和C1-6烷氧基。另外优选地，R2和R2'各自为H；R3为H；R6各自独立地选自卤素和C1-6烷氧基。
在其他优选的实施方式中，R1和R1'各自独立地选自H、C1-3烷基、氨基、C1-3氨基烷基、羟基、C1-3羟基烷基、C1-3烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；R2和R2'各自为H，或连接在一起形成亚乙基；R3选自H、羟基、和氟；R4各自独立地选自卤素、C1-3烷基、C1-3卤代烷基、C3-5环烷基、C3-5环烷基C1-3烷基、C1-3羟基烷基、四氢呋喃基、四氢吡喃基、吗啉-4基乙基、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；R5各自独立地选自C1-C2烷基、C1-C2羟基烷基和C1-C2烷氧基羰基；R6各自独立地选自氟、氯、氨基和C1-3烷氧基。
在优选的方面，本发明涉及一种作为SHP2抑制剂的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物，所述化合物如式Ia所示：
其中，A、n、R1和R1'、R2和R2'、R3、R4、以及R5如上所定义。
优选地，A选自苯基、咪唑并吡啶基(例如咪唑并[4,5-b]吡啶基，特别是)、噁二唑基(例如[1,2,4]噁二唑-3-基，特别是)、噁唑基和异噁唑基(例如异噁唑-3-基，特别是)；
n为1或2；
R1和R1'各自独立地选自C1-6烷基、C1-6氨基烷基、和羟基，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；
R2和R2'各自为H，或连接在一起形成C2-4亚烷基(优选亚乙基)；
R3为H；
R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C3-6环烷基C1-6烷基、苯基、和5或6元杂环烷基(优选四氢呋喃基)；
R5为C1-C4烷基(优选甲基)；
R6选自卤素和C1-6烷氧基。
进一步优选地，A为咪唑并吡啶基，优选咪唑并[4,5-b]吡啶基，更优选地选自
另外进一步优选地，R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被卤素或C1-6烷氧基取代，更优选地被氟或甲氧基取代。
在另外优选的方面，本发明涉及一种作为SHP2抑制剂的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物，所述化合物如式Ib所示：
其中，A、n、R1和R1'、R2和R2'、R3、以及R4如上所定义。
优选地，A选自苯基、咪唑并吡啶基(例如咪唑并[4,5-b]吡啶基，特别是)、噁二唑基(例如[1,2,4]噁二唑-3-基，特别是)、噁唑基和异噁唑基(例如异噁唑-3-基，特别是)；
n为1或2；
R1和R1'各自独立地选自H、C1-6烷基、氨基、C1-6氨基烷基、羟基、C1-6羟基烷基、C1-6烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；
R2和R2'各自为H，或连接在一起形成C2-4亚烷基(优选亚乙基)；
R3选自H、羟基、和卤素；
R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C1-6羟基烷基、5或6元杂环烷基(优选四氢呋喃基或四氢吡喃基)、5或6元杂环烷基 C1-6烷基(优选吗啉-4基乙基)、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；
R6各自独立地选自卤素和C1-6烷氧基。
进一步优选地，A为咪唑并吡啶基，优选咪唑并[4,5-b]吡啶基，更优选
另外进一步优选地，R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被C1-6烷氧基取代，更优选地被甲氧基取代。
在其他优选的方面，本发明涉及一种作为SHP2抑制剂的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物，所述化合物如式Ic所示：
其中，A、n、R1和R1'、R2和R2'、R3、以及R5如上所定义。
优选地，A选自咪唑并吡啶基(例如咪唑并[4,5-b]吡啶基，特别是)、噁二唑基(例如[1,2,4]噁二唑-3-基，特别是)、噁唑基和异噁唑基(例如异噁唑-3-基，特别是)；
n为1或2；
R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；
R2和R2'各自为H；
R3为H；
R4各自独立地选自C1-6卤代烷基、C3-6环烷基、和任选地被1至3个R6取代的苯基、和吡啶基；
R5选自C1-C4羟基烷基和C1-C4烷氧基羰基；
R6各自独立地选自卤素、氨基和C1-6烷氧基。
进一步优选地，A为咪唑并吡啶基，优选咪唑并[4,5-b]吡啶基，更优选
另外进一步优选地，R5是C1-C4羟基烷基，更优选羟甲基。
另一方面，本申请还提供包括式I、Ia、Ib或Ic的化合物或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物、和药学上可接受的稀释剂或载体、以及任选的其他活性药物成分的药物组合物。
在其他方面，本申请还涉及式I、Ia、Ib或Ic的化合物或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物用于抑制SHP2活性的方法和用途。
在另一方面，本申请还涉及式I、Ia、Ib或Ic的化合物或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物用于治疗、预防或缓和由SHP2介导的疾病的方法和用途。在优选的方面，所述疾病选自癌症、癌症转移、心血管疾病、免疫疾病、纤维化或眼部疾病。在更优选的方面，所述疾病选自癌症，特别是选自青少年髓单核细胞白血病、神经母细胞瘤、黑色素瘤、头颈部鳞状细胞癌、急性髓性白血病、乳腺癌、食道肿瘤、肺癌、结肠癌、头癌、胃癌、淋巴瘤、胶质母细胞瘤、胰腺癌或其组合的癌症。
在其他方面，本申请还涉及式I、Ia、Ib或Ic的化合物或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物在制备用于治疗、预防或缓和由SHP2介导的疾病的药物中的用途。在优选的方面，所述疾病选自癌症、癌症转移、心血管疾病、免疫疾病、纤维化或眼部疾病。在更优选的方面，所述疾病选自癌症，特别是选自青少年髓单核细胞白血病、神经母细胞瘤、黑色素瘤、头颈部鳞状细胞癌、急性髓性白血病、乳腺癌、食道肿瘤、肺癌、结肠癌、头癌、胃癌、淋巴瘤、胶质母细胞瘤、胰腺癌或其组合的癌症。
具体实施方式
术语
除非另外定义，所有本文使用的科技术语都具有与要求保护的主题所属领域的技术人员一般理解相同的含义。
除非另有说明，本发明采用本领域技术范围内的质谱、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学等常规方法。除非提供具体的定义，否则与本文描述的分析化学、合成有机化学、以及医学和药物化学等化学上相关的命名和实验室操作和技术，是本领域技术人员已知的。一般而言，前述技术和步骤可以通过本领域众所周知的和在各种一般文献和更具体文献中描述的常规方法来实施，这些文献在本说明书中被引用和讨论。
术语“烷基”是指脂肪族烃基团，可以是支链或直链的烷基。根据结构，烷基可 以是单价基团或双价基团(即亚烷基)。在本发明中，烷基优选是具有1-8个碳原子的烷基，更优选具有1-6个碳原子的“低级烷基”，甚至更优选具有1-4个碳原子的烷基。典型的烷基包括但不限于甲基、乙基、丙基、丁基、戊基、己基等。应理解，本文提到的“烷基”包括可能存在的所有构型和构象的该烷基，例如本文提到的“丙基”包括正丙基和异丙基，“丁基”包括正丁基、异丁基和叔丁基，“戊基”包括正戊基、异戊基、新戊基、叔戊基、和戊-3-基等。
术语“烷氧基”是指-O-烷基，其中烷基如本文中定义。典型的烷氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等。
术语“烷氧基烷基”是指本文定义的烷基被本文定义的烷氧基取代。
术语“环烷基”是指单环或多环基，其仅含有碳和氢。环烷基包括具有3-12个环原子的基团。根据结构，环烷基可以是单价基团或双价基团(例如亚环烷基)。在本发明中，环烷基优选是具有3-8个碳原子的环烷基，更优选具有3-6个碳原子的“低级环烷基”。环烷基的例子包括但不限于，环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环戊烯基、环己烯基、环庚烯基和金刚烷基。
术语“烷基(环烷基)”或“环烷基烷基”是指本文定义的烷基被本文定义的环烷基取代。非限制性的环烷基烷基包括环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基等。
术语“芳香基”是指平面环具有离域的π电子***并且含有4n+2个π电子，其中n是整数。芳香基环可以由五、六、七、八、九或多于九个原子构成。芳香基可以是任选取代的。术语“芳香基”包括碳环芳基(例如苯基)和杂环芳基(或“杂芳基”或“杂芳香基”)基团(例如吡啶)。该术语包括单环或稠环多环(即共用相邻的碳原子对的环)基团。
本文使用的术语“芳基”是指芳香基环中每一个构成环的原子都是碳原子。芳基环可以由五、六、七、八、九或多于九个原子构成。芳基可以是任选取代的。芳基的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。根据结构，芳基可以是单价基团或双价基团(即亚芳基)。
术语“芳氧基”是指-O-芳基，其中芳基如本文中定义。
术语“杂芳基”是指芳基中包括一个或多个选自氮、氧和硫的环杂原子。含N“杂芳基”部分是指芳香基中环上至少有一个骨架原子是氮原子。根据结构，杂芳基可以是单价基团或双价基团(即亚杂芳基)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、***基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、吲唑基、吲嗪基、酞嗪基、哒嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、萘啶基和呋喃并吡啶基等。
术语“烷基(芳基)”或“芳烷基”是指本文定义的烷基被本文定义的芳基取代。非 限制性的烷基(芳基)包括苄基、苯乙基等。
术语“烷基(杂芳基)”或“杂芳基烷基”是指本文定义的烷基被本文定义的杂芳基取代。
本文使用的术语“杂烷基”是指本文定义的烷基中的一个或多个骨架链原子是杂原子，例如氧、氮、硫、硅、磷或它们的组合。所述杂原子(一个或多个)可以位于杂烷基内部的任意位置或在杂烷基与分子的其余部分相连的位置。
本文使用的术语“杂环烷基”或“杂环基”是指非芳香基环中一个或多个构成环的原子是选自氮、氧和硫的杂原子。杂环烷基环可以是由三、四、五、六、七、八、九或多于九个原子构成的单环或多环。杂环烷基环可以是任选取代的。杂环烷基的实例包括但不限于内酰胺、内酯、环亚胺、环硫代亚胺、环氨基甲酸酯、四氢噻喃、4H-吡喃、四氢吡喃、哌啶、1,3-二噁英、1,3-二噁烷、1,4-二噁英、1,4-二噁烷、哌嗪、1,3-氧硫杂环己烷、1,4-氧硫杂环己二烯、1,4-氧硫杂环己烷、四氢-1,4-噻嗪、2H-1,2-噁嗪、马来酰亚胺、琥珀酰亚胺、巴比妥酸、硫代巴比妥酸、二氧代哌嗪、乙内酰脲、二氢尿嘧啶、吗啉、三噁烷、六氢-1,3,5-三嗪、四氢噻吩、四氢呋喃、吡咯啉、吡咯烷、咪唑烷，吡咯烷酮、吡唑啉、吡唑烷、咪唑啉、咪唑烷、1,3-二氧杂环戊烯、1,3-二氧杂环戊烷、1,3-二硫杂环戊烯、1,3-二硫杂环戊烷、异噁唑啉、异噁唑烷、噁唑啉、噁唑烷、噁唑烷酮、噻唑啉、噻唑烷和1,3-氧硫杂环戊烷。根据结构，杂环烷基可以是单价基团或双价基团(即亚杂环烷基)。
术语“烷基(杂环烷基)”或“杂环烷基烷基”是指本文定义的烷基被本文定义的杂环烷基取代。
术语“烷氧基(杂环烷基)”或“杂环烷基烷氧基”是指本文定义的烷氧基被本文定义的杂环烷基取代。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“卤代烷基”、“卤代烷氧基”和“卤代杂烷基”包括烷基、烷氧基或杂烷基的结构，其中至少一个氢被卤原子置换。在某些实施方式中，如果两个或更多氢原子被卤原子置换，所述卤原子彼此相同或不同。
术语“噁二唑基”是指包括1,2,4-噁二唑基、1,2,5-噁二唑基和1,3,4-噁二唑基等异构体形式的噁二唑基。
术语“噁唑基”是指包括1,2-噁唑基(异噁唑基)、1,3-噁唑基等异构体形式的噁唑基。
术语“羟基”是指-OH基团。
术语“氰基”是指-CN基团。
术语“酯基”是指具有式-COOR的化学部分，其中R选自烷基、环烷基、芳基、杂芳基(通过环碳连接)和杂环基(通过环碳连接)。
术语“氨基”是指-NH2基团。
术语“氨酰基”是指-CO-NH2基团。
术语“烷基氨酰基”是指-CO-NH-R基团，其中R为本文定义的烷基。
术语“酰胺基”或“酰氨基”是指-NR-CO-R’，其中R和R’各自独立地为氢或烷基。
术语“烷基氨基”是指进一步被一个或两个烷基取代的氨基取代基，具体是指基团-NRR’，其中R和R’各自独立地选自氢或低级烷基，条件是-NRR’不是-NH2。“烷基氨基”包括其中-NH2的氮连接至少一个烷基基团的化合物的基团。烷基氨基基团的例子包括但不限于，甲基氨基、乙基氨基等。“二烷基氨基”包括其中-NH2的氮连接至少两个其它烷基基团的基团。二烷基氨基基团的例子包括但不限于，二甲基氨基、二乙基氨基等。
术语“芳基氨基”和“二芳基氨基”是指进一步被一个或两个芳基取代的氨基取代基，具体是指基团-NRR’，其中R和R’各自独立地选自氢、低级烷基、或芳基，其中N分别连接至少一个或两个芳基基团。
术语“环烷基氨基”是指进一步被一个或两个本文所定义的环烷基取代的氨基取代基。
术语“杂烷基氨基”是指进一步被一个或两个本文所定义的杂烷基取代的氨基取代基。
本文的术语“芳烷基氨基”是指其中R是低级芳烷基且R’是氢、低级烷基、芳基或低级芳烷基的基团-NRR’。
术语“杂芳基氨基”是指进一步被一个或两个本文所定义的杂芳基取代的氨基取代基。
术语“杂环烷基氨基”是指本文定义的氨基被本文定义的杂环烷基取代。
术语“烷基氨基烷基”是指本文定义的烷基被本文定义的烷基氨基取代。
术语“氨基烷基”是指进一步被一个或多个氨基取代的烷基取代基。
术语“氨基烷氧基”是指进一步被一个或多个氨基取代的烷氧基取代基。
术语“羟烷基”或“羟基烷基”是指进一步被一个或多个羟基取代的烷基取代基。
术语“氰基烷基”是指进一步被一个或多个氰基取代的烷基取代基。
术语“酰基”是指有机或无机含氧酸去掉羟基后剩下的一价原子团，通式为R-M(O)-，其中M通常为C。
术语“羰基”是由碳和氧两种原子通过双键连接而成的有机官能团(C＝O)。
术语“烷酰基”或“烷基羰基”是指进一步被一个烷基取代的羰基。典型的烷酰基包括但不限于乙酰基、丙酰基、丁酰基、戊酰基、己酰基等。
术语“芳基羰基”是指本文定义的羰基被本文定义的芳基取代。
术语“烷氧基羰基”是指进一步被一个烷氧基取代的羰基。
术语“杂环烷基羰基”是指进一步被一个杂环烷基取代的羰基。
术语“烷基氨基羰基”、“环烷基氨基羰基”、“芳基氨基羰基”、“芳烷基氨基羰基”、“杂芳基氨基羰基”分别是指本文定义的羰基分别被本文定义的烷基氨基、环 烷基氨基、芳基氨基、芳烷基氨基、或杂芳基氨基取代。
术语“烷基羰基烷基”或“烷酰基烷基”是指进一步被一个烷基羰基取代的烷基。
术语“烷基羰基烷氧基”或“烷酰基烷氧基”是指进一步被一个烷基羰基取代的烷氧基。
术语“杂环烷基羰基烷基”是指进一步被一个杂环烷基羰基取代的烷基。
术语“巯基”是指-SH基团。术语“烷硫基”是指本文所定义的巯基被本文所定义的烷基取代。
术语“砜基”或“磺酰基”是指磺酸失去羟基后的官能团，具体是指-S(＝O)2-基团。
术语“亚砜基”或“亚磺酰基”是指-S(＝O)-。
术语“氨基砜基”或“氨基磺酰基”是指-S(＝O)2-NH2基团。
术语“烷基亚砜基”或“烷基亚磺酰基”是指烷基-S(＝O)-。
术语“烷基砜基”或“烷基磺酰基”是指-S(＝O)2-R，其中R为烷基。
术语“烷基氨基砜基”是指本文定义的砜基被本文定义的烷基氨基取代。
术语“烷基砜基氨基”或“烷基磺酰氨基”，以及“环烷基砜基氨基”或“环烷基磺酰氨基”是指本文定义的氨基被本文定义的烷基砜基或环烷基砜基取代，即-NH-S(＝O)2-R，其中R分别为烷基和环烷基。
术语“环烷基砜基”和“环烷基磺酰基”是指-S(＝O)2-R，其中R为环烷基。
术语“季铵基”是指-N+RR’R”，其中R、R’和R”各自独立地选自具有1-8个碳原子的烷基。
术语“任选”指后面描述的一个或多个事件可以发生或可以不发生，并且包括发生的事件和不发生的事件两者。术语“任选取代的”或“取代的”是指所提及的基团可以被一个或多个额外的基团取代，所述额外的基团各自并且独立地选自烷基、环烷基、芳基、杂芳基、杂环基、羟基、烷氧基、氰基、卤素、酰胺基、硝基、卤代烷基、氨基、甲磺酰基、烷基羰基、烷氧基羰基、杂芳基烷基、杂环烷基烷基、氨酰基、氨基保护基等。其中，氨基保护基优选选自新戊酰基、叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、苄基、对甲氧苄基、烯丙氧羰基、和三氟乙酰基等。
本文术语“药学上可接受的盐”指的是保留主题化合物的所需生物学活性且显示最小的不希望的毒理学效应的盐。这些药学上可接受的盐可以在化合物的最终分离和纯化过程中原位制备，或通过单独使纯化化合物的游离酸或游离碱形式分别与合适的碱或酸反应来制备。
“溶剂化物”或“溶剂合物”指的是含有化学计量或非化学计量溶剂的溶剂加成形式。一些化合物趋于以晶状固态捕集固定摩尔比例的溶剂分子，从而形成溶剂合物。若溶剂是水，则形成的溶剂合物是水合物；若溶剂是醇，则形成的溶剂合物是醇化物。水合物通过使一个或多个水分子与所述物质的一个分子结合而形成，其中所述水保持其分子状态为H2O。
本文公开的化合物的“代谢物”是当该化合物被代谢时形成的化合物的衍生物。 术语“活性代谢物”是指当该化合物被代谢时形成的化合物的生物活性衍生物。本文使用的术语“被代谢”，是指特定物质被生物体改变的过程总和(包括但不限于水解反应和由酶催化的反应，例如氧化反应)。因此，酶可以产生特定的结构转变为化合物。例如，细胞色素P450催化各种氧化和还原反应，同时二磷酸葡萄糖甘酸基转移酶催化活化的葡萄糖醛酸分子至芳香醇、脂肪族醇、羧酸、胺和游离的巯基的转化。新陈代谢的进一步的信息可以从《The Pharmacological Basis of Therapeutics》，第九版，McGraw-Hill(1996)获得。本文公开的化合物的代谢物可以通过将化合物给予宿主并分析来自该宿主的组织样品、或通过将化合物与肝细胞在体外孵育并且分析所得化合物来鉴别。这两种方法都是本领域已知的。在一些实施方式中，化合物的代谢物是通过氧化过程形成并与相应的含羟基化合物对应。在一些实施方式中，化合物被代谢为药物活性代谢物。
本文使用的术语“调节”，是指直接或间接与靶标相互作用，以改变靶标的活性，仅仅举例来说，包括增强靶标的活性、抑制靶标的活性、限制靶标的活性或者延长靶标的活性。
术语“前药”或“前体药物”是指如下衍生物，其可能不具有药理学活性，但在某些情况下，可口服或肠胃外给予并在这之后在体内代谢以形成具有药理学活性的本发明化合物。前药的非限制性实例包括：酯、碳酸酯、半酯、磷酸酯、硝基酯、硫酸酯、亚砜、酰胺、氨基甲酸酯、含氮化合物、磷酰胺、糖苷、醚、乙缩醛和酮缩醇等。
“有效量”指，将引发例如研究者或医师在研的组织、***、动物或人的生物学或医学反应的药物或药学制剂的量。此外，术语“治疗有效量”指与没有接受该量的相应对象相比，引起疾病、紊乱、或副作用改良的治疗、治愈、预防、或缓解、或者疾病或紊乱发展速率降低的任何量。该术语范围内还包括有效提高正常生理功能的量。
本文所用的术语“治疗”指缓解疾病、紊乱或病症的至少一种症状。该术语包括向对象给药和/或应用一种或多种本文所述化合物以提供病症的管理或治疗。用于本公开目的的“治疗”可以但不必须提供治愈；而是指，“治疗”可以是病症的管理形式。当本文所述化合物用于处理有害的增殖细胞(包括癌)时，“治疗”包括部分或完全破坏所述有害的增殖细胞，但对正常细胞的破坏影响最小。有害的快速增殖细胞(包括癌细胞)的所需处理机制在细胞水平上是凋亡。
本文所用的术语“预防”包括共同预防或减缓临床上显著疾病发展的开始或者预防或减缓风险个体中的临床前显著疾病阶段的开始。这包括预防性治疗有疾病发展风险的个人。
术语“受试者”或“患者”包括能患有病症或与降低的或不足的程序性细胞死亡(细胞凋亡)相关的病症的有机体或能以其他方式从本发明化合物的给药中获益的有机体，例如人类和非人类动物。优选的人类包括患有或倾向患有如本文所述 的病症或相关状况的人类患者。术语“非人类动物”包括脊椎动物，例如哺乳动物，如非人类灵长类动物、羊、牛、狗、猫和啮齿动物如小鼠，以及非哺乳动物，如鸡、两栖动物、爬行动物等。
本文使用的GI50是指使50％细胞生长被抑制所需的药物浓度，即药物使50％细胞(如癌细胞)的生长得到抑制或控制时的药物浓度。
本文使用的IC50是指在测量效应的分析中获得最大效应的50％抑制的特定测试化合物的量、浓度或剂量。
本文使用的EC50是指测定化合物的剂量、浓度或量，其引起特定测定化合物诱导、刺激或加强的特定反应的50％的最大表达的剂量依赖反应。
本发明的激酶抑制剂
本发明涉及一种SHP2抑制剂，其包括如式I所述的化合物、或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物：
其中，
A为芳基或杂芳基，优选地选自苯基、咪唑并吡啶基(例如咪唑并[4,5-b]吡啶基，特别是)、噁二唑基(例如[1,2,4]噁二唑-3-基，特别是)、噁唑基和异噁唑基(例如异噁唑-3-基，特别是)；
B为含氮不饱和单环或双环，优选地选自吡嗪(例如)、吡唑并嘧啶酮(例如)、和吡唑并吡嗪(例如)；
m和n各自独立地为0、1或2；
R1和R1'各自独立地选自H、C1-6烷基、氨基、C1-6氨基烷基、羟基、C1-6羟基烷基、C1-6烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1至3个R6取代；
R2和R2'各自为H，或连接在一起形成C2-4亚烷基；
R3选自H、羟基、和卤素；
R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C3-6环烷基C1-6烷基、C1-6羟基烷基、5或6元杂环烷基、5或6元杂环烷基C1-6烷基、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；
R5各自独立地选自C1-C4烷基、C1-C4羟基烷基和C1-C4烷氧基羰基；
R6各自独立地选自卤素、氨基和C1-6烷氧基。
优选地，R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；更优选地R1和R1'一起形成 当存在R6时，R6选自卤素(例如氟)和C1-6烷氧基(例如甲氧基)。
在其他优选的实施方式中，R1和R1'各自独立地选自H、C1-3烷基、氨基、C1-3氨基烷基、羟基、C1-3羟基烷基、C1-3烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；R2和R2'各自为H，或连接在一起形成亚乙基；R3选自H、羟基、和氟；R4各自独立地选自卤素、C1-3烷基、C1-3卤代烷基、C3-5环烷基、C3-5环烷基C1-3烷基、C1-3羟基烷基、四氢呋喃基、四氢吡喃基、吗啉-4基乙基、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；R5各自独立地选自C1-C2烷基、C1-C2羟基烷基和C1-C2烷氧基羰基；R6各自独立地选自氟、氯、氨基和C1-3烷氧基。
另外优选地，R2和R2'各自为H；R3为H；R6各自独立地选自卤素和C1-6烷氧基。
在优选的方面，本发明涉及一种SHP2抑制剂，其包括式Ia所示的化合物、或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物：
其中，A、n、R1和R1'、R2和R2'、R3、R4、以及R5如上所定义。
优选地，A选自苯基、和咪唑并吡啶基(例如咪唑并[4,5-b]吡啶基，特别是)、噁二唑基(例如[1,2,4]噁二唑-3-基，特别是)、噁唑基和异噁唑基(例如异噁唑-3-基，特别是)；
n为1或2；
R1和R1'各自独立地选自C1-6烷基、C1-6氨基烷基、和羟基，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；
R2和R2'各自为H，或连接在一起形成C2-4亚烷基(优选亚乙基)；
R3为H；
R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C3-6环烷基C1-6烷基、苯基、和5或6元杂环烷基(优选四氢呋喃基)；
R5为C1-C4烷基(优选甲基)；
R6选自卤素和C1-6烷氧基。
进一步优选地，A为咪唑并吡啶基，特别是咪唑并[4,5-b]吡啶基，更特别地选自另外优选地，R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被卤素(例如氟)或C1-6烷氧基(例如甲氧基)取代。
特别优选地，本发明涉及下表1所列的式I或式Ia所示的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物。
表1
在另外优选的方面，本发明涉及一种SHP2抑制剂，其包括如式Ib所示的化合物、或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物：
其中，A、n、R1和R1'、R2和R2'、R3、以及R4如上所定义。
优选地，A选自苯基、咪唑并吡啶基(例如咪唑并[4,5-b]吡啶基，特别是)、和噁二唑基(例如[1,2,4]噁二唑-3-基，特别是)、噁唑基和异噁唑基(例如异噁唑-3-基，特别是)；
n为1或2；
R1和R1'各自独立地选自H、C1-6烷基、氨基、C1-6氨基烷基、羟基、C1-6羟基烷基、C1-6烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；
R2和R2'各自为H，或连接在一起形成C2-4亚烷基(优选亚乙基)；
R3选自H、羟基、和卤素；
R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C1-6羟基烷基、5或6元杂环烷基(优选四氢呋喃基或四氢吡喃基)、5或6元杂环烷基C1-6烷基(优选吗啉-4基乙基)、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；
R6各自独立地选自卤素和C1-6烷氧基。
进一步优选地，A为咪唑并吡啶基，特别是咪唑并[4,5-b]吡啶基，更特别是另外优选地，R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被C1-6烷氧基(例如甲氧基)取代。
特别优选地，本发明涉及下表2所列的式I或式Ib所示的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物。
表2

在其他优选的方面，本发明涉及一种SHP2抑制剂，其包括式Ic所示的化合物、或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物：
其中，A、n、R1和R1'、R2和R2'、R3、以及R5如上所定义。
优选地，A选自咪唑并吡啶基(例如咪唑并[4,5-b]吡啶基，特别是)、噁二唑基(例如[1,2,4]噁二唑-3-基，特别是)、噁唑基和 异噁唑基(例如异噁唑-3-基，特别是)；
n为1或2；
R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；
R2和R2'各自为H；
R3为H；
R4各自独立地选自C1-6卤代烷基、C3-6环烷基、和任选地被1至3个R6取代的苯基、和吡啶基；
R5选自C1-C4羟基烷基和C1-C4烷氧基羰基；
R6各自独立地选自卤素、氨基和C1-6烷氧基。
进一步优选地，A为咪唑并吡啶基，特别是咪唑并[4,5-b]吡啶基，更特别是另外优选地，R5是C1-C4羟基烷基，特别是羟甲基。
特别优选地，本发明涉及下表3所列的式I或式Ic所示的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物。
表3

对于各个变量，上述基团的任意组合也在本文考虑之中。可以理解的是：本文所提供的化合物上的取代基和取代模式可以由本领域技术人员进行选择，以便提供化学上稳定的且可以使用本领域已知的技术以及本文阐述的技术合成的化合物。
本文也描述了此化合物的药学可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物。
在另外的或进一步的实施方式中，将本文描述的化合物给予有需要的生物体后在其体内代谢产生代谢物，所产生的代谢物然后用于产生期望的效果，包括期望的治疗效果。
本文描述的化合物可以被制成和/或被用作药学可接受的盐。药学可接受的盐的类型包括但不限于：(1)酸加成盐，通过将化合物的游离碱形式与药学可接受的无机酸反应形成，所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸、偏磷酸等；或与有机酸反应形成，所述有机酸如乙酸、丙酸、己酸、环戊烷丙酸、羟基乙酸、丙酮酸、乳酸、丙二酸、苹果酸、柠檬酸、琥珀酸、马来酸、酒石酸、反丁烯二酸、三氟乙酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、甲苯磺酸、4-甲基双环-[2.2.2]辛-2-烯-1-甲酸、2-萘磺酸、叔丁基乙酸、葡庚糖酸、4,4'-亚甲基双-(3-羟基-2-烯-1-甲酸)、3-苯基丙酸、三甲基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、水杨酸、羟基萘酸、硬脂酸、粘康酸等；(2)碱加成盐，其在母体化合物中的酸性质子被金属离子置换时形成，例如碱金属离子(例如锂、钠、钾)、碱土金属离子(例如镁或钙)或铝离子；或与有机碱或无机碱配位，可接受的有机碱包括乙醇胺、二乙醇胺、三乙醇胺、三甲胺、N-甲基葡萄糖胺等；可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠、氢氧化钠等。
药学可接受的盐的相应的平衡离子可以使用各种方法分析和鉴定，所述方法包括但不限于离子交换色谱、离子色谱、毛细管电泳、电感耦合等离子体、原子吸收光谱、质谱或它们的任何组合。
使用以下技术的至少一种回收所述盐：过滤、用非溶剂沉淀接着过滤、溶剂蒸发，或水溶液的情况下使用冻干法。
筛选和表征药学可接受的盐、多晶型和/或溶剂化物可以使用多种技术完成，所述技术包括但不限于热分析、X射线衍射、光谱、显微镜方法、元素分析。使用的各种光谱技术包括但不限于Raman、FTIR、UVIS和NMR(液体和固体状态)。各种显微镜技术包括但不限于IR显微镜检术和拉曼(Raman)显微镜检术。
本发明的药物用途
本发明的式I、Ia、Ib或Ic的化合物或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物，能够抑制SHP2活性，从而达到治疗、预防或缓和由SHP2介导的疾病的的目的。在优选的方面，
因此，本申请要保护式I、Ia、Ib或Ic的化合物或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物，在制备用于抑制SHP2活性、或治疗、预防或缓和由SHP2介导的疾病的药物中的用途。
优选地，所述疾病选自癌症、癌症转移、心血管疾病、免疫疾病、纤维化或眼部疾病。
更优选地，所述疾病选自癌症，特别是选自青少年髓单核细胞白血病、神经母细胞瘤、黑色素瘤、头颈部鳞状细胞癌、急性髓性白血病、乳腺癌、食道肿瘤、肺癌、结肠癌、头癌、胃癌、淋巴瘤、胶质母细胞瘤、胰腺癌或其组合的癌症。
在本发明的实施方式中，可以通过注射、口服、吸入、直肠和经皮施用中的至少一种将包含本发明化合物的药物施用给患者。在根据本发明对患者进行治疗时，给定药物的量取决于诸多因素，如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重)，但是，根据特定的周围情况，包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主，施用剂量可由本领域已知的方法常规决定。通常，就成人治疗使用的剂量而言，施用剂量典型地在0.02-5000mg/天，例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量，例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是，尽管给出了上述剂量范围，但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
化合物的制备
使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本文描述的方法组合，可以合成本发明的化合物。另外，本文给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。作为进一步的指导，也可以利用以下的合成方法。
所述反应可以按顺序使用，以提供本文描述的化合物；或它们可以用于合成片段，所述片段通过本文描述的方法和/或本领域已知的方法随后加入。
在某些实施方式中，本文提供的是本文描述的酪氨酸激酶抑制剂化合物的制备方法及其使用方法。在某些实施方式中，本文描述的化合物可以使用以下合成的方案合成。可以使用与下述类似的方法，通过使用适当的可选择的起始原料，合成化合物。
用于合成本文描述的化合物的起始原料可以被合成或可以从商业来源获得。 从商业购买的原料未进行进一步纯化，除非另有说明。本文描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本文公开的化合物的一般方法可以来自本领域已知的反应，并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改，以引入本文提供的分子中的各种部分。
如果需要，反应产物可以使用常规技术分离和纯化，包括但不限于过滤、蒸馏、结晶、色谱等方法。这些产物可以使用常规方法表征，包括物理常数和图谱数据。
柱层析色谱采用青岛化工有限公司生产的硅胶(200-300目)，薄层色谱采用青岛化工生产的硅胶板，核磁共振色谱使用布鲁克核磁共振仪，液质联用(LCMS)使用安捷伦1200系列液相质谱仪。
实施例的合成中使用了如下缩略词：
DCM：二氯甲烷
ACN：乙腈
DIEPA：N,N-二异丙基乙胺
DME：乙二醇二甲醚
DMF：N,N-二甲基甲酰胺
DMAc：二甲基乙酰胺
DMAP：4-二甲氨基吡啶
DMSO：二甲基亚砜
EA：乙酸乙酯
LCMS：液相色谱-质谱联用
TEA：三乙胺
PE：石油醚
TFA：三氟乙酸
Ti(OEt)4：钛酸四乙酯
TLC：薄层色谱
DAST:：二乙胺基三氟化硫
THP：四氢吡喃
DHP：3,4-二氢-2H-吡喃
NIS：N-碘代丁二酰亚胺
NBS:N-溴代丁二酰亚胺
NMO：N-甲基吗啉N-氧化物
LDA：二异丙基氨基锂
Ar：氩气。
中间体化合物IM1的合成：
步骤1：化合物IM1-3的合成
室温下，将化合物IM1-1(10g)、IM1-2(19.8g)溶于DMF中，降温至0℃，N2保护，分批向其中加入氢化钠(9g)。加完后，保温搅拌反应30-40分钟，升温至60℃，搅拌反应12-16小时。LCMS监测显示原料消失，降温至0℃，向其中滴加水淬灭反应。加入EA萃取反应液两次，水洗有机相两次，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析分离得目标物3.83g。
步骤2：化合物IM1-4的合成
室温下，将化合物IM1-3(3.83g)、R-叔丁基亚磺酰胺(4g)溶于钛酸四乙酯中，升温至90℃搅拌反应12-16小时。LCMS监测显示反应完全，降温室温，向其中加入水，EA萃取反应液两次，水洗有机相两次，无水硫酸钠干燥30分钟，过滤，浓缩得目标物3.1g。
步骤3：化合物IM1-5的合成
室温下，将化合物IM1-4(3.1g)，溶于THF中，分批加入硼氢化钠(0.33g)，室温搅拌反应12-14小时。LCMS监测显示反应完全，向其中加入饱和氯化铵水溶液淬灭反应液，EA萃取反应液两次，水洗有机相两次，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析得目标物2.5g。
步骤4：化合物IM1的合成
室温下，将化合物IM1-5(2.5g)溶于DCM中，加入三氟乙酸(0.66mL)，室温搅拌反应5-7小时。LCMS监测显示反应完全，减压浓缩除去溶剂和多余的三氟乙酸。向其中加入饱和碳酸氢钠水溶液中和反应液，EA萃取反应液两次，水洗有机相两次，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析得目标物1.5g。[M+H]+325.20。
参考以上方法合成如下中间体：
中间体化合物IM5的合成：
步骤1：化合物IM5-2的合成
向100mL单口烧瓶中加入IM5-1(2.5g,10.55mmol)、SM(1.5g,11.6mmol)、碳酸铯(6.86g,21.1mmol)，室温(10℃)下向其中加入无水DMF，升温至60℃(内温)，搅拌反应1小时。LCMS监测显示原料消耗完全，降温，EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩得目标物2.51g。
步骤2～3：化合物IM5-4的合成
向100mL单口烧瓶中加入IM5-2(0.7g,2.11mmol)，向其中加入TFA(5.0mL)，加入铁粉(0.6g)，搅拌反应3小时。LCMS检测显示原料消耗完全，用磁吸棒将铁粉吸附除去后，升温至回流，反应10小时，LCMS监测显示反应完全。减压浓缩除去溶剂，EA稀释残留物，饱和碳酸氢钠溶液中和反应液，分液，无水硫酸钠干燥有机相，过滤浓缩的目标物，不纯化直接进行下一步反应。
步骤4：化合物IM5的合成
向100mL单口烧瓶中加入IM5-4(0.57g,1.5mmol)、联硼酸频哪醇酯(0.76 g,3.0mmol)、醋酸钾(0.36g,3.76mmol)、Pd(dppf)Cl2DCM(0.25g,0.3mmol)，N2置换4-5次，室温(30℃)下负压下抽入二氧六环，升温至100℃，搅拌反应12小时。LCMS监测显示原料消耗完全，降温，EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩，制得棕黑色油状目标物0.6g，收率87％。[M+H]+427.2202。
参考以上方法合成如下中间体：
中间体化合物IM13、IM14：
中间体化合物IM15的合成：
步骤1：化合物IM15-2的合成
向100mL圆底烧瓶中加入IM15-1(50mg)、NIS(145mg)、1mL乙腈。混合物在85℃反应2小时。TLC监控反应终点(PE/EA＝5/1)，显示反应完毕。反应液冷却至室温然后抽滤，滤饼旋干得黄色固体90mg，收率：99％。[M+H]+280.8。
步骤2：化合物IM15的合成
称取IM15-2(90mg)于100mL圆底烧瓶，加DCM(1mL)溶解，然后加入DHP(81mg)、TsOH(16.6mg)，混合物在25℃反应10分钟。TLC监控反应终点(PE/EA＝20/1)，显示反应完毕，反应液加NaHCO3淬灭。用DCM进行萃取，滤液旋干得粗品。粗品柱层析(PE/EA＝20/1)得白色固体40mg，收率：34％。[M+H]+364.9。
中间体化合物IM16的合成：
步骤1：化合物IM16-2的合成
称取IM16-1(1.0g,5.3mmol)于100mL圆底烧瓶，加DCM(5.0mL)溶解，然后加入DHP(0.49g,5.82mmol)、TsOH(91mg,0.53mmol)，混合物在25℃反应20分钟。TLC监控反应终点(PE/EA＝20/1)，显示反应完毕。反应液加NaHCO3淬灭，然后用DCM进行萃取，滤液旋干得粗品。粗品柱层析(PE/EA＝20/1)得 白色固体900mg，收率：34％。[M+H]+274.12。
步骤2：化合物IM16-3的合成
室温下，将化合物IM16-2(900mg,3.3mmol)、氢氧化钠(0.53g,13.2mmol)溶于四氢呋喃(5mL)中，升温至80-90℃搅拌反应12-16小时，LCMS监测显示反应完全。降温室温，向其中加入水，EA萃取反应液两次，水洗有机相两次，无水硫酸钠干燥30分钟，过滤，浓缩得目标物0.7g。
步骤3：化合物IM16-4的合成
室温下，将化合物IM16-3(0.7g,2.74mmol)、K2CO3(0.76g,5.50mmol)溶于THF中，加入碘甲烷(0.5g,3.57mmol)，55-60℃搅拌反应12-14小时，LCMS监测显示反应完全。向其中加入饱和氯化铵水溶液淬灭反应液，EA萃取反应液两次，水洗有机相两次，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析得目标物0.85g。
步骤4：化合物IM16的合成
向100mL圆底烧瓶中加入IM16-4(0.85g,3.16mmol)、NIS(0.78g,3.48mmol)、ACN(6.0mL)。混合物在85℃反应2小时。TLC监控反应终点(PE/EA＝5/1)，显示反应完毕。反应液冷却至室温然后抽滤，滤饼旋干得黄色固体90mg。[M+H]+395.60。
实施例1化合物1的合成
步骤1：化合物1-1的合成
称取化合物IM16(200mg)于50mL圆底烧瓶中，加入IM18(234.4mg)、CsF(210.2mg)，室温下加入无水DMAc(2mL)溶解，置于80℃油浴中搅拌反应1小时，TLC监测反应终点(展开剂：MeOH/DCM＝1/20)。反应液中加入乙酸乙酯，用水洗两次，饱和食盐水洗一次，有机相用无水硫酸钠干燥，减压旋干后拌样柱层析，得中间体1-1共计430mg，收率99％。质谱：[M+H]+645.29。
步骤2：化合物1-2的合成
称取化合物1-1(430mg)于100mL圆底烧瓶中，加入二氯苯硼酸(148.1mg)，室温下加入Pd(dppf)Cl2(74.8mg)、磷酸钾(178.8mg)、二氧六环(5mL)和水(0.5mL)，氩气置换三次后，置于100℃油浴中搅拌反应16小时。TLC监测反应终点(展开剂：MeOH/DCM＝1/12.5)。减压旋干反应液后拌样柱层析，得中间体1-2共计300mg，收率65％，[M+H]+683.23。
步骤3：化合物1的合成
称取化合物1-2(300mg)于100mL圆底烧瓶中，室温下加入甲醇(10mL)，搅拌下缓慢加入盐酸/甲醇溶液(4N,10mL)，室温下搅拌反应16小时。LCMS监测反应终点，反应液减压旋干，加入饱和碳酸钠水溶液中和，再用二氯甲烷萃取三次后，合并有机相用无水硫酸钠干燥。旋干后用制备板分离纯化，得终产品70mg，收率32％。质谱：[M+H]+495.19；1H NMR(DMSO-d6,500MHz)δ13.60(s,1H),7.73(dd,J＝7.4,2.2Hz,1H),7.51–7.37(m,3H),7.32–7.17(m,3H),4.08(s,1H),3.54–3.44(m,2H),3.40(s,3H),3.05(d,J＝14.6Hz,2H),2.75(d,J＝15.9Hz,1H),2.00–1.83(m,2H),1.56(d,J＝13.3Hz,1H),1.32(d,J＝12.9Hz,1H)。
实施例2：化合物2的合成
步骤1：化合物2-1的合成
称取IM16(100mg，0.25mmol)、IM13(69mg，0.30mmol)、DIPEA(66mg，0.50mmol)于100mL圆底烧瓶中，然后加DMF(2mL)溶解，混合物在60℃油浴中反应6小时。TLC监控反应终点(DCM/MeOH＝20/1)，显示反应完毕。反应液加入水中析出黄色固体，抽滤，滤饼旋干得粗品无色油状物2-1粗品110mg，收率74％，[M+H]+587.21。
步骤2：化合物2-2的合成
称取2-1(110mg，0.19mmol)、三丁基乙烯基锡(322mg，0.28mmol)、Pd(PPh3)4(43.4mg，0.038mmol)，TEA(38mg，0.37mmol)于100mL圆底烧 瓶中，然后加DMF(5mL)溶解，混合物用氩气置换3次气体后置于110℃油浴中反应12小时。TLC监控反应终点(DCM/MeOH＝40/1)，反应约12小时后显示反应完毕。反应液用硅藻土抽滤，滤液旋干得粗品。粗品柱层析分离(DCM/MeOH＝40/1)得黄色油状物80mg，收率：88％。[M+H]+487.61。
步骤3：化合物2-3的合成
称取2-2(80mg，0.16mmol)、K2OsO4·2H2O(5.5mg，0.016mmol)、NaIO4(35mg，0.16mmol)，于100mL圆底烧瓶中，然后加THF(2mL)和H2O(2mL)溶解，混合物在25℃反应12小时。TLC监控反应终点(DCM/MeOH＝20/1)，反应约12小时后显示反应完毕。反应液加亚硫酸氢钠水溶液淬灭，然后用EA萃取，有机相旋干得粗品90mg，不纯化直接进行下一步。[M+H]+488.6。
步骤4：化合物2-4的合成
称取2-3(90mg，0.18mmol)、盐酸羟胺NH2OH·HCl(14.1mg，0.21mmol)于100mL圆底烧瓶中，然后加EtOH(1mL)溶解，混合物在25℃反应12小时。TLC监控反应终点(DCM/MeOH＝20/1)，反应约12小时后显示反应完毕。反应液加水淬灭，然后用DCM进行萃取，有机相旋干得粗品。粗品柱层析分离(DCM/MeOH＝20/1)得黄色固体60mg，[M+H]+503.3。
步骤5：化合物2-5的合成
称取2-4(60mg，0.12mmol)于25mL圆底烧瓶中，加MeOH(3mL)和H2O(0.6mL)溶解，然后加入苯乙炔(6mg，0.24mmol)、PhI(AcO)2(57.6mg，0.18mmol)，混合物在25℃反应12小时。TLC监控反应终点(DCM/MeOH＝40/1)，反应约12小时后显示反应完毕。反应液旋干得粗品。粗品柱层析分离(DCM/MeOH＝20/1)得无色油状物31mg，[M+H]+604.30。
步骤6：化合物2的合成
称取化合物2-5(31mg)于100mL圆底烧瓶中，室温下加入甲醇(4mL)，搅拌下缓慢加入盐酸/甲醇溶液(4N，4mL)，室温下搅拌反应16小时。LCMS监测反应终点，反应液减压旋干，加入饱和碳酸钠水溶液中和，再用二氯甲烷萃取三次后，合并有机相用无水硫酸钠干燥。旋干后用制备板分离纯化，得终产品10mg。质谱：[M+H]420.2。
实施例3：化合物3的合成
步骤1：化合物3-1的合成
参考化合物2-1的合成方法经由中间体IM16和IM13合成得到，质谱[M+H]587.2。
步骤2：化合物3-2的合成
向100mL单口烧瓶中加入3-1(100mg，0.16mmol)、Zn(CN)2(28.28mg，0.24mmol)、Pd2(dba)3(14.8mg，0.016mmol)、Pd(dppf)Cl2DCM(13.2mg，0.016mmol)，室温(30℃)下向其中加入水/DMF(2/14mL)，升温至110℃(内温)，搅拌反应5小时。LCMS监测显示原料消耗完全，降温。EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析得目标物78mg。[M+H]+486.3。
步骤3：化合物3-3的合成
向100mL单口烧瓶中加入3-2(78mg，0.15mmol)、盐酸羟胺(15.3mg，0.22mmol)、碳酸氢钠(24.6mg，0.29mmol)，加入乙醇搅拌反应12小时。LCMS监测显示原料反应完全，EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次。合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩得目标物0.1g。[M+H]+519.3。
步骤4：化合物3-4的合成
向100mL单口烧瓶中加入3-3(0.10g，0.19mmol)、苯甲酰氯(32.74mg，0.23mmol)、TEA(23.57mg，0.23mmol)、甲苯(3mL)，0℃搅拌反应1小时，升温至回流搅拌反应12小时。LC-MS监测显示原料消耗完全，降温。EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩。柱层析(PE/EA 5:1)制得目标物50mg，[M+H]+605.3。
步骤5：化合物3的合成
向100mL单口烧瓶中加入3-4(50mg)，室温(30℃)下加入盐酸甲醇(3mL)，搅拌反应2-3小时，LCMS监测显示原料消耗完全。向反应液中加入饱和碳酸氢钠溶液中和，加入乙酸乙酯(10mL)并萃取反应液，水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟。过滤，浓缩，柱层析(DCM/MeOH 20:1) 并冻干得类白色目标物8mg。质谱：[M+H]421.2。
经由不同的起始原料和相应的试剂，采用与前述实施例1相似的方法合成得到下列目标物。



实施例7：化合物7的合成
步骤1：化合物7-1的合成
向250mL三口瓶中加入THF(80mL)和SM2(3g)，开启搅拌，Ar置换三次后降温至-40℃，缓慢滴加甲基溴化镁(溶于THF,1.0mol/L,63mL)，滴毕于-40℃下继续搅拌约30分钟后置于室温反应。TLC监控反应终点(PE/EA＝5/1)，反应约2小时后显示反应完毕。将反应液缓慢加入至约100mL饱和氯化铵溶液中，分液，有机相用水洗涤2次，饱和食盐水洗涤1次，无水硫酸钠干燥，过滤，EA洗涤滤饼，滤液真空浓缩至干得产物2.59g，收率：80％。[M+H]+232。
步骤2：化合物7-2的合成
向50mL单口瓶中加入7-1(0.5g)、Pd/C(50mg)和10mL甲醇，开启搅拌，氢气置换三次后于室温过夜反应。LC-MS监控反应终点，反应约16小时后显示反应完毕。硅藻土过滤去除Pd/C，滤饼用甲醇洗涤2次，合并洗滤液真空浓缩至干得粗品0.43g。[M+H]+142。
步骤3：化合物7-3的合成
向10mL反应管中加入7-2(100mg)、IM16(43mg)、碳酸钾(173mg)和DMF(2mL)，开启搅拌，升温至60℃反应。LC-MS监控反应终点，反应约2小时后显示反应完毕。降至室温后加水淬灭，DCM萃取3次，有机相用水洗涤3次，饱和食盐水洗涤1次，无水硫酸钠干燥，过滤，滤饼DCM洗涤，合并洗滤液真空浓缩至干得粗品70mg。[M+H]+500。
步骤4：化合物7-4的合成
向10mL封管中加入7-3(70mg)、二氯苯硼酸(33mg)、PdCl2(dppf)(23mg)、碳酸钾(58mg)、二氧六环(2mL)和水(0.5mL)，氩气置换后于搅拌状态下升温至90℃反应。TLC监控反应终点(PE/EA＝1/1)，反应约2小时后显示反应完毕。降至室温后加水淬灭，DCM萃取3次，有机相用饱和食盐水洗涤1次，无水硫酸钠干燥，过滤，滤饼DCM洗涤。合并洗滤液真空浓缩至干，柱层析(PE/EA＝1/1)，得产物31mg，收率：43％。[M+H]+518。
步骤5：目标化合物7的合成
向25mL反应瓶中加入7-4(31mg)和TFA(5mL)，开启搅拌于室温反应。LC-MS监控反应终点，反应约2小时后显示反应完毕。真空浓缩除尽TFA，加入碳酸钠水溶液，DCM萃取三次，饱和碳酸氢钠溶液洗涤一次，无水硫酸钠干燥，过滤，滤饼DCM洗涤，柱层析(PE/EA＝1/1)，得产物12mg，收率：46％。[M+H]+434。1H NMR(500MHz,DMSO)δ13.40(s,1H),7.71(dd,J＝7.3,2.3Hz,1H),7.48–7.35(m,2H),4.22(d,J＝13.0Hz,3H),3.39(s,3H),2.22(d,J＝6.8Hz,2H),1.98–1.85(m,4H),1.77(d,J＝13.2Hz,2H),1.12(s,3H)。
实施例15：化合物15的合成：
参考实施例2的合成方法，经由中间体IM15、IM13合成得到该化合物，[M+H]390.2。
经由不同的起始原料和相应的试剂，采用与前述实施例1相似的方法合成得到下列目标物。





实施例19：化合物19的合成
步骤1：化合物19-1的合成
向250mL三口瓶中加入THF(80mL)和SM2(3g)，开启搅拌，Ar气置换三次后降温至-40℃，缓慢滴加甲基溴化镁(溶于THF，1.0mol/L，63mL)，滴毕于-40℃下继续搅拌约30分钟后置于室温反应。TLC监控反应终点(PE/EA＝5/1)，反应约2小时后显示反应完毕。将反应液缓慢加入至约100mL饱和氯化铵溶液中，分液，有机相用水洗涤2次，饱和食盐水洗涤1次，无水硫酸钠干燥，过滤，EA洗涤滤饼，滤液真空浓缩至干得产物2.59g，收率：80％。[M+H]+232。
步骤2：化合物19-2的合成
向100mL单口瓶中加入19-1(1.65g)和50mL乙腈，开启搅拌，冰浴下缓慢滴加浓硫酸(7mL)，滴加完毕后撤除冰浴，置于室温反应。LCMS监控反应进程，反应约3小时后显示反应完毕。将反应液置于冰浴中，缓慢加饱和碳酸钠水溶液调节反应液pH至碱性，采用EA萃取三次，合并有机相用水洗涤3次，饱和食盐水洗涤1次，无水硫酸钠干燥，过滤，滤饼用EA洗涤两次，合并洗滤液真空浓缩至干得粗品0.86g，[M+H]+273。
步骤3：化合物19-3的合成
向50mL单口瓶中加入19-2(220mg)，Pd/C(25mg)和甲醇(5mL)，开启搅拌，氢气置换三次后于室温过夜反应。LC-MS监控反应终点，反应约5小时后显示反应完毕。硅藻土过滤去除Pd/C，滤饼用甲醇洗涤2次，合并洗滤液真空浓缩至干得粗品165mg，[M+H]+183。
步骤4：化合物19-4的合成
向25mL单口瓶中加入19-3(109mg)、IM15(66mg)、碳酸钾(124mg)和DMF(3mL)，开启搅拌，升温至60℃反应。LC-MS监控反应终点，反应约16小时后显示反应完毕。降至室温后加水淬灭，DCM萃取3次，有机相用水洗涤3次，饱和食盐水洗涤1次，无水硫酸钠干燥，过滤，滤饼DCM洗涤。合并洗滤液真空浓缩至干后柱层析(PE/EA＝1/3)，得产物56mg，收率37％。[M+H]+511。
步骤5：化合物19-5的合成
向10mL封管中加入19-4(56mg)、二氯苯硼酸(23mg)、PdCl2(dppf)(16 mg)、碳酸钾(42mg)、二氧六环(2mL)和水(0.5mL)，氩气置换后于搅拌状态下升温至90℃反应，LC-MS监控反应终点，反应约16小时后显示反应完毕。降至室温后加水淬灭，DCM萃取3次，有机相用饱和食盐水洗涤1次，无水硫酸钠干燥，过滤，滤饼DCM洗涤。合并洗滤液真空浓缩至干，柱层析(PE/EA＝1/2)，得产物23mg，收率：39％。[M+H]+529。
步骤6：化合物19的合成
向25mL单口瓶中加入19-5(23mg)和TFA(5mL)，开启搅拌于室温反应。LC-MS监控反应终点，反应约14小时后显示反应完毕。真空浓缩除尽TFA，加入碳酸钠水溶液，DCM萃取三次，饱和碳酸氢钠溶液洗涤一次，无水硫酸钠干燥，过滤，滤饼DCM洗涤。柱层析(PE/EA＝1/2)，得产物16mg，收率：83％。[M+H]+445。1H NMR(500MHz,DMSO-d6)δ13.39(s,1H),8.28(s,1H),7.72(ddd,J＝17.3,7.9,1.5Hz,2H),7.61(s,1H),7.49(t,J＝7.9Hz,1H),4.68(s,2H),2.53(d,J＝14.9Hz,2H),2.13(d,J＝7.5Hz,2H),2.00–1.88(m,2H),1.83(s,3H),1.65(d,J＝12.8Hz,2H),1.09(s,3H)。
实施例20：化合物20的合成
步骤1：化合物SM1的合成
向100mL单口烧瓶中加入SM1-1(5.0g)、二氯甲烷(5mL)，室温(30℃)下向其中加入无水三氟乙酸(2mL)，搅拌反应1小时，LCMS监测显示原料消耗完全。减压浓缩除去二氯甲烷和三氟乙酸，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析(PE/EA 5:1)制得淡黄色目标物4.0g，收率81％。
步骤2：化合物20-1的合成
向100mL单口烧瓶中加入SM1(71.7mg)、IM15(0.1g)、碳酸钾(77.1mg)，室温(30℃)下向其中加入无水DMF，升温至60℃(内温)，搅拌反应5小时，TLC监测(PE/EA 5:1)显示原料消耗完全。降温，EA(5mL)稀释反应液，加入 水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析(PE/EA 5:1)制得淡黄色目标物0.1g，收率83％。
步骤3：化合物20-2的合成
向100mL单口烧瓶中加入二氯苯硼酸(50.51mg)、20-1(0.1g)、磷酸钾(60.98mg)、Pd(dppf)Cl2(5.4mg)，N2置换4-5次，室温(30℃)下负压下抽入二氧六环/水混合溶剂，升温至80-85℃(内温)，搅拌反应5小时。TLC监测(PE/EA 5:1)显示原料消耗完全，降温，EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩。柱层析(PE/EA2:1)制得淡黄色目标物0.09g，收率90％。[M+H]+472。
步骤4：化合物20-3的合成
向100mL单口烧瓶中加入20-2(90mg)，室温(30℃)下加入盐酸甲醇溶液，并搅拌反应2-3小时，TLC监测(PE/EA 5:1)显示原料消耗完全。向反应液中加入饱和碳酸氢钠溶液中和反应液，加入EA(5mL)萃取反应液两次，水(10mL)洗涤有机相1次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩。柱层析(DCM/MeOH 20:1)并冻干得类白色目标物30mg，收率40.5％。[M+H]+388.0763。1H NMR(500MHz,DMSO-d6)δ13.58(s,1H),8.49(s,1H),7.73(ddd,J＝21.7,7.8,1.6Hz,2H),7.50(t,J＝7.9Hz,1H),4.98(s,2H),2.74(dd,J＝15.6,4.4Hz,2H),2.32(d,J＝15.6Hz,2H),2.15(d,J＝9.8Hz,2H),1.76(d,J＝7.6Hz,3H)。
步骤5：化合物20的合成
向100mL单口烧瓶中加入20-3(30mg)，室温(30℃)下加入THF(2mL)，加入硼氢化钠(5mg)并搅拌反应2-3小时，TLC监测(PE/EA 5:1)显示原料消耗完全。向反应液中加入饱和氯化铵溶液淬灭反应。加入水、EA(5mL)萃取反应液两次，水(10mL)洗涤有机相2次，合并有机相，无水硫酸镁干燥30分钟，过滤，浓缩。柱层析(DCM/MeOH 10:1)并冻干得类白色目标物9mg，收率30％。[M+H]+390.0876。1H NMR(500MHz,DMSO-d6)δ13.44(s,1H),8.31(s,1H),7.72(ddd,J＝22.1,7.9,1.6Hz,2H),7.49(t,J＝7.9Hz,1H),4.71(q,J＝4.0,3.3Hz,2H),4.43(d,J＝6.3Hz,1H),4.04(dq,J＝10.8,5.3Hz,1H),2.00(dd,J＝8.6,4.1Hz,2H),1.92–1.77(m,4H),1.51(t,J＝11.6Hz,2H)。
实施例21：化合物21的合成
步骤1：化合物SM1的合成
参考上述实施例20中间体SM1的合成方法。
步骤2：化合物21-1的合成
向100mL单口烧瓶中加入SM1(0.36g)、IM15(0.5g)、碳酸钾(0.39g)，室温(30℃)下向其中加入无水DMF，升温至60℃(内温)，搅拌反应5小时，TLC监测(PE/EA 5:1)显示原料消耗完全。降温，EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析(PE/EA 5:1)制得淡黄色目标物0.45g，收率62％。
步骤3：化合物21-2的合成
向100mL单口烧瓶中加入二氯苯硼酸(45.45mg)、21-1(90mg)、碳酸钾(55.12mg)、Pd(dppf)Cl2DCM(0.51mg)，N2置换4-5次，室温(30℃)下负压下抽入二氧六环/水混合溶剂，升温至80-85℃(内温)，搅拌反应5小时，TLC监测(PE/EA 5:1)显示原料消耗完全。降温，EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩。柱层析(PE/EA 5:1)制得淡黄色目标物78mg，收率96％。[M+H]+472.1312。
步骤4.中间体21-3的合成
向250mL三口烧瓶中加入KOH(10.8mg)、甲醇(2mL)，0℃搅拌。向其中滴加21-2的甲醇溶液(1mL)，滴加完成后保温反应25分钟，加入醋酸碘苯(20.84mg)，保温反应3-4小时。LCMS监测显示反应完全。向反应液中加入乙酸乙酯(10mL)、水(10mL)萃取反应液两次，水(10mL)洗涤有机相1次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩，不进一步纯化，下一步直接使用。[M+H]+534.1670。
步骤5.化合物21的合成
向100mL单口烧瓶中加入21-3(90mg)，室温(30℃)下加入二氯甲烷溶解，并加入三氟乙酸(2mL)，搅拌反应2-3小时，TLC监测(PE/EA 1:1)显示原料消耗完全。减压浓缩除去溶剂和三氟乙酸，向反应液中加入乙酸乙酯(10mL)，饱和碳酸氢钠溶液中和并萃取反应液，水(10mL)洗涤有机相1次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩。柱层析(DCM/MeOH 10:1)并冻干得类白色目标物7mg，收率11％。[M+H]+404.0717。1H NMR(500MHz,DMSO-d6)δ13.60(s,1H),8.50(s,1H),7.73(ddd,J＝21.8,7.8,1.6Hz,2H),7.50(t,J＝7.9Hz,1H),5.61(d,J＝4.9Hz,1H),4.97(t,J＝6.0Hz,1H),4.84(t,J＝5.8Hz,1H),4.14(d,J＝5.5Hz,1H),2.83(d,J＝15.4Hz,1H),2.36(dd,J＝14.7,1.8Hz,1H),2.14–2.07(m,1H),2.00–1.90(m,2H),1.62(ddd,J＝13.5,9.6,4.6Hz,1H)。
实施例28：化合物28的合成
步骤1：化合物28-1的合成
向50mL三口烧瓶中加入21-3(100mg)、DCM(2mL)，0℃搅拌。向其中滴加DAST(60.33mg，0.37mmol)，滴加完成后转移至室温(25℃)反应2小时。取样LCMS监测显示反应完全，室温浓缩至干，向其中加入乙酸乙酯(10mL)、碳酸氢钠水溶液(10mL)萃取反应液两次，水(10mL)洗涤有机相1次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩。柱层析制得80mg，收率70％。[M+H]+536.15。
步骤2：化合物28-2的合成
向100mL单口烧瓶中加入28-1(80mg)，室温(30℃)下加入二氯甲烷溶解，并加入三氟乙酸(2mL)，搅拌反应2-3小时。TLC监测(PE/EA 1:1)显示原料消耗完全。减压浓缩除去溶剂和三氟乙酸，向反应液中加入乙酸乙酯(10mL)， 饱和碳酸氢钠溶液中和并萃取反应液，水(10mL)洗涤有机相1次，合并有机相，无水硫酸钠干燥30分钟。过滤，浓缩，柱层析(DCM/MeOH 10:1)并冻干得类白色目标物60mg，收率54％。[M+H]+406.0642。1H NMR(500MHz,DMSO-d6)δ13.62(s,1H),8.47(s,1H),7.73(ddd,J＝31.6,7.8,1.6Hz,2H),7.50(t,J＝7.9Hz,1H),5.13(s,1H),4.95(dt,J＝10.3,4.9Hz,1H),4.86(dt,J＝7.7,4.2Hz,2H),2.87(dd,J＝18.3,7.4Hz,1H),2.56(d,J＝18.3Hz,1H),2.18–2.09(m,1H),2.08–1.98(m,1H),1.90–1.70(m,2H)。
步骤3：化合物28-3的合成
向100mL单口烧瓶中加入28-2(0.16g)、叔丁基亚磺酰胺(57.14mg)、钛酸四乙酯(0.58g，33％)，室温(25℃)下向其中加入无水THF，升温至80℃(内温)，搅拌反应12-16小时。LCMS监测显示原料消耗完全，降温，向其中加入NaBH4，25℃反应5小时，LCMS监测显示反应完全。EA(5mL)稀释反应液，加入水(10mL)，有大量固体析出，过滤，水洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟。过滤，浓缩得目标物粗品0.1g。[M+H]+511.12499。
步骤4：化合物28的合成
向100mL单口烧瓶中加入28-3(100mg)，室温(30℃)下加入盐酸甲醇溶液，搅拌反应2-3小时。TLC监测(PE/EA 1:1)显示原料消耗完全，减压浓缩，向反应液中加入乙酸乙酯(10mL)，饱和碳酸氢钠溶液中和并萃取反应液，水(10mL)洗涤有机相1次，合并有机相，无水硫酸钠干燥30分钟。过滤，浓缩，柱层析(DCM/MeOH 10:1)并冻干得类白色目标物8mg，收率10％。[M+H]+407.0978。1H NMR(500MHz,DMSO-d6)δ13.48(s,1H),8.30(s,1H),7.71(ddd,J＝31.5,7.9,1.6Hz,2H),7.49(t,J＝7.9Hz,1H),4.87(dd,J＝10.9,6.2Hz,1H),4.82–4.66(m,3H),3.82(dt,J＝11.5,5.8Hz,1H),2.57–2.52(m,1H),2.45–2.32(m,1H),2.04(dd,J＝12.7,6.2Hz,1H),1.89(d,J＝18.8Hz,1H),1.76–1.66(m,1H),1.54(dd,J＝13.1,5.9Hz,1H)。
实施例29：化合物29的合成
步骤1：化合物29-1的合成
参考化合物1-1的合成方法经由中间体IM15和IM18合成得到，[M+H]635。
步骤2：化合物29-2的合成
向100mL单口烧瓶中加入29-1(100mg，0.16mmol)、Zn(CN)2(28.28mg，0.24mmol)、Pd2(dba)3(14.8mg，0.016mmol)、Pd(dppf)Cl2DCM(13.2mg，0.016mmol)，室温(30℃)下向其中加入水/DMF(2/14mL)，升温至110℃(内温)，搅拌反应5小时。LCMS监测显示原料消耗完全，降温。EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩，柱层析得目标物78mg。[M+H]+534.2648。
步骤3：化合物29-3的合成
向100mL单口烧瓶中加入29-2(78mg，0.15mmol)、盐酸羟胺(15.3mg，0.22mmol)、碳酸氢钠(24.6mg，0.29mmol)，加入乙醇搅拌反应12小时。LCMS监测显示原料反应完全，EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次。合并有机相，无水硫酸钠干燥30min，过滤，浓缩得目标物0.12g。[M+H]+679.2788。
步骤4：化合物29-4的合成
向100mL单口烧瓶中加入29-3(0.12g，0.21mmol)、苯甲酰氯(32.74mg，0.23mmol)、TEA(23.57mg，0.23mmol)、甲苯(3mL)，0℃搅拌反应1小时，升温至回流搅拌反应12小时。LC-MS监测显示原料消耗完全，降温。EA(5mL)稀释反应液，加入水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟，过滤，浓缩。柱层析(PE/EA 5:1)制得目标物50mg，收率25％。[M+H]+653.3330。
步骤5：化合物29的合成
向100mL单口烧瓶中加入29-4(50mg)，室温(30℃)下加入盐酸甲醇(3mL)，搅拌反应2-3小时，LCMS监测显示原料消耗完全。向反应液中加入饱和碳酸氢钠溶液中和，加入乙酸乙酯(10mL)并萃取反应液，水(10mL)洗涤有机相2次，合并有机相，无水硫酸钠干燥30分钟。过滤，浓缩，柱层析(DCM/MeOH20:1)并冻干得类白色目标物10mg。HPLC 99.4％，[M+H]+465.2185。1H NMR(500MHz,DMSO-d6)δ8.68(s,1H),8.32–8.25(m,2H),7.76(t,J＝7.6Hz,2H),7.38(d,J＝6.5Hz,1H),7.28–7.23(m,3H),5.39(t,J＝5.1Hz,2H),4.44(s,2H),3.94(s,1H),3.25–3.16(m,3H),2.74(d,J＝15.7Hz,1H),2.08(d,J＝7.4Hz,2H),1.91–1.88(m,1H),1.67–1.61(m,2H)。
实施例30：化合物30的合成
按照与实施例29相似的方法合成化合物30。[M+H]+533.14。1H NMR(500MHz,DMSO-d6)δ8.64(s,1H),8.16(dd,J＝7.9,1.6Hz,1H),8.03(dd,J＝8.1,1.6Hz,1H),7.67(t,J＝8.0Hz,1H),7.42–7.33(m,1H),7.27–7.21(m,3H),5.32(t,J＝5.1Hz,1H),4.43–4.35(m,2H),4.04(s,1H),3.15(d,J＝15.8Hz,1H),2.79(d,J＝15.8Hz,1H),1.98(q,J＝6.6,5.1Hz,2H),1.79–1.71(m,1H),1.58(d,J＝13.3Hz,1H)。
经由不同的起始原料和相应的试剂，采用与前述实施例29相似的方法合成得到下列目标物。

实施例40：化合物40的合成
步骤1：化合物40-1的合成
于100mL单口瓶中加入原料SM2(3g)，并用50mL DMSO溶解，随后加入Me3SI(3g)，在搅拌下缓慢加入叔丁醇钾(1.65g)。加料完毕后，于25℃下搅拌反应1小时。TLC检测，以PE:EA＝5:1为展开剂，原料无剩余。向反应液中加入水淬灭反应，并加入石油醚萃取，合并有机相，依次用水洗，饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩，得白色固体目标产物3g，收率为94.6％。[M+H]+230。
步骤2：化合物40-2的合成
将原料40-1(400mg)溶于10mL的7M NH3甲醇溶液中，并将反应液转移至封管中于80℃下搅拌反应16小时。TLC检测，以DCM:MeOH＝10:1为展开剂，原料无剩余。将反应液直接浓缩至干，并用DCM带除残留的NH3，浓缩后静置一段时间，得黄色固体400mg，收率94％。[M+H]+247。
步骤3：化合物40-3的合成
于25mL单口瓶中将原料40-2(150mg)溶于无水THF(5mL)中，随后加入三乙胺(82.2mg)及DMAP(10mg)，于25℃下搅拌活化10分钟后。加入的Boc2O(106mg)，并继续在25℃下搅拌反应2小时。LCMS检测原料无剩余，且产物峰为主要信号峰，将反应液加水淬灭，并用DCM萃取。合并有机相，依次用水洗，饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩得粗品。柱层析纯化，以PE:EA＝5:1为展开剂，得黄色油状物170mg，收率81％。[M+H]+347。
步骤4：化合物40-4的合成
于50mL单口瓶中加入原料40-3(170mg)，随后加入无水甲醇(15mL)溶解，并加入的Pd/C(20mg)。于氢气球保护下，在25℃下搅拌反应20小时，LCMS 检测原料无剩余。硅藻土抽滤，收集滤液，浓缩，即得目标产物120mg，为黄色油状物。收率95.2％，[M+H]+257。
步骤5：化合物40-5的合成
于50mL单口瓶中加入原料40-4(120mg)及IM15(222mg)并用DMF(10mL)溶解，加入碳酸钾(195mg)后，升温至60℃搅拌反应3小时。LCMS检测原料无剩余，TLC检测以PE:EA＝2:1为展开剂。向反应液中加入水淬灭反应，并用EA萃取，合并有机相，依次用水洗，饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩得粗品。柱层析纯化，以PE:EA＝2:1为展开剂，得纯化后产物150mg，收率55％。[M+H]+585。
步骤6：化合物40-6的合成
于50mL单口瓶中加入原料40-5(150mg)，用二氧六环(20mL)及水(2mL)混合溶剂溶解，随后加入的二氯苯硼酸(59mg)、钯催化剂(20mg)及碳酸钾(106mg)，氩气置换三次保护下，升温至90℃下搅拌反应16小时。LCMS检测原料无剩余且有产物峰出现，将反应液直接浓缩至干。柱层析纯化，以PE:EA＝2:1为展开剂，得纯化后产物100mg，收率为65％。[M+H]+603。
步骤7：化合物40的合成
于50mL单口瓶中加入原料40-6(100mg)，随后加入4M HCl甲醇溶液(10mL)溶解原料，并于25℃下搅拌反应2小时。LCMS检测，原料无剩余。将反应液直接浓缩至干，随后加入饱和碳酸钠溶液调节pH＝8～9，并用乙酸乙酯萃取，合并有机相。依次用水洗，饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩即得粗品60mg。将粗品柱层析纯化，以DCM:MeOH＝5:1为展开剂，收集目标化合物，浓缩后用乙腈/水的混合溶剂冻干，得纯化后白色固体目标化合物30mg，收率43.4％。[M+H]+419.6192。1H NMR(500MHz,DMSO-d6)δ8.26(s,1H),7.75(d,J＝7.8Hz,1H),7.66(d,J＝7.7Hz,1H),7.51(t,J＝7.9Hz,1H),4.76(p,J＝3.1Hz,2H),2.51(s,2H),2.29(d,J＝7.3Hz,2H),1.97(t,J＝5.9Hz,2H),1.79(q,J＝14.1Hz,4H)。
实施例41：化合物41的合成
步骤1：化合物41-1的合成
于25mL单口瓶中加入原料40-1(300mg)并溶解于水(5mL)中，随后缓慢加入浓硫酸(0.5mL)，滴加完毕后于25摄氏度下搅拌反应16小时。LCMS检测有产物峰，用饱和碳酸钠溶液淬灭并调节pH＝10，随后加入EA萃取。合并有机相，依次用水洗，饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩即得产物为黄色油状物200mg，收率为62.5％。[M+H]+248。
步骤2：化合物41-2的合成
于50mL单口瓶中将原料41-1(200mg)溶于无水甲醇(15mL)中，随后加入Pd/C(30mg)，在氢气球保护下于25℃下搅拌反应20小时。LCMS检测，原料无剩余。将反应液用硅藻土过滤，收集滤液浓缩至干即得产物为黄色油状物70mg，收率95％。[M+H]+158。
步骤3：化合物41-3的合成
于50mL单口瓶中加入原料41-2(70mg)，随后加入DMF(15mL)溶解，并加入IM15(149mg)、碳酸钾(170mg)，于60℃下搅拌反应16小时。TLC检测原料无剩余，LCMS检测有产物主峰出现，将反应液加水淬灭。EA萃取，浓缩有机相，柱层析纯化，以纯EA为展开剂，得目标产物黄色固体50mg，收率27％。[M+H]+486。
步骤4：化合物41-4的合成
于50mL单口瓶中加入原料41-3(50mg)并用二氧六环(10ml)及水(2mL)的混合溶剂溶解。加入二氯苯硼酸(23mg)、碳酸钾(42mg)、钯催化剂(10mg)，氩气保护下于90℃下搅拌反应4小时。LC-MS检测，原料无剩余。将反应液浓缩至干，柱层析纯化，以纯EA为展开剂，得产物20mg，收率40％。[M+H]+504。
步骤5：化合物41的合成
于50mL单口瓶中加入原料41-4(320mg)，随后加入4M HCl甲醇溶液(10mL)溶解，并于25℃下搅拌反应2小时。LCMS检测原料无剩余。将反应液直接浓缩至干，随后加入饱和碳酸钠溶液调节pH＝8～9，并用乙酸乙酯萃取。合并有机相，依次用水洗，饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩即得粗品。将粗品柱层析纯化，以纯EA为展开剂，收集目标化合物，浓缩后用乙腈/水的混合溶剂冻干，纯化后得白色固体目标化合物12mg，收率90.4％。[M+H]+420.1989。1H NMR(500MHz,DMSO-d6)δ13.34(s,1H),8.25(s,1H),7.72(ddd,J＝16.0,7.9,1.6Hz,2H),7.48(t,J＝7.9Hz,1H),4.71(d,J＝5.0Hz,2H),4.52(t,J＝5.7Hz,1H),4.23(s,1H),2.87(d,J＝5.6Hz,2H),2.33(d,J＝7.1Hz,2H),2.03–1.97(m,2H),1.92(d,J＝8.4Hz,2H),1.47(d,J＝14.0Hz,2H)。
实施例47：化合物47的合成
按照与实施例28中化合物28-2相同的方法合成。[M+H]+406.0642。1H NMR(500MHz,DMSO-d6)δ13.62(s,1H),8.47(s,1H),7.73(ddd,J＝31.6,7.8,1.6Hz,2H),7.50(t,J＝7.9Hz,1H),5.13(s,1H),4.95(dt,J＝10.3,4.9Hz,1H),4.86(dt,J＝7.7,4.2Hz,2H),2.87(dd,J＝18.3,7.4Hz,1H),2.56(d,J＝18.3Hz,1H),2.18–2.09(m,1H),2.08–1.98(m,1H),1.90–1.70(m,2H)。
实施例48：化合物48的合成
步骤1：化合物48-1的合成
向100mL圆底烧瓶中加入SM3(20g，270mmol)于250mL圆底烧瓶中，加入EtOH(176mL)溶解。反应物置于0℃冰水浴中，然后滴加酮基丙二酸二乙酯(47g，270mmol)，反应液在25℃反应1.5小时，反应液变成乳白色，然后置于85℃油浴中反应20小时。TLC监控反应终点(DCM/MeOH＝20/1)，反应约20小时后显示反应完毕。反应液直接减压旋干,然后硅胶拌样柱层析分离(PE/EA＝20/1～2/1)得黄色固体48-1共计9.1g，收率：20％。
步骤2：化合物48-2的合成
称取48-1(1g，5.49mmol)于100mL圆底烧瓶，加POCl3(5mL)溶解，混合物在110℃反应12小时。TLC监控反应终点(PE/EA＝2/1)，反应约12小时后显示反应完毕。反应液慢慢加入水中淬灭，然后用NaOH调pH至中性。然后用EA进行萃取，有机相旋干得粗品。粗品柱分离(PE/EA＝20/1～5/1)得黄色油状物48-2共计0.3g，收率：30％。1H NMR(500MHz,CDCl3)δ8.45(s,1H),4.50(q,J＝7.1Hz,2H),2.69–2.61(m,3H),1.45(t,J＝7.1Hz,3H)。
步骤3：化合物48-3的合成
称取48-2(123mg，0.61mmol)、IM2(200mg，0.61mmol)、DIPEA(394mg，3.05mmol)于100mL圆底烧瓶中，然后加DMF(2mL)溶解，混合物在60℃油浴中反应6小时。TLC监控反应终点(DCM/MeOH＝20/1)，显示反应完毕。反应液加入水中析出黄色固体，抽滤，滤饼旋干得粗品无色油状物48-3粗品201mg,收率：66％。[M+H]+501.25。
步骤4：化合物48-4的合成
称取48-3(201mg，0.402mmol)于100mL圆底烧瓶中，然后加DCM(2mL)溶解，分批加入NBS(101mg，0.603mmol)，混合物在25℃反应1小时。TLC监控反应终点(DCM/MeOH＝20/1)，反应约1小时后显示反应完毕。反应液加Na2SO3溶液淬灭，然后用DCM进行萃取，有机相旋干得粗品。粗品柱层析分离(DCM/iPrOH＝15/1)无色油状物99mg，收率：52％。[M+H]+475.11。
步骤5：化合物48-5的合成
称取48-4(99mg，0.209mmol)、TEA(25mg，0.25mmol)于100mL圆底烧瓶中，然后加2mL DCM溶解，然后慢慢加入Boc2O(55mg，0.25mmol)，混合物在25℃反应12小时。TLC监控反应终点(DCM/MeOH＝20/1)，反应约12小时后显示反应完毕。反应液加水淬灭，然后用DCM进行萃取，有机相旋干得粗品。粗品柱层析分离(DCM/MeOH＝20/1)得淡黄色固体64mg 48-5，收率：53％。[M+H]+574.2/577.2。
步骤6：化合物48-6的合成
称取48-5(390mg，0.678mmol)、三丁基乙烯基锡(322mg，1.017mmol)、Pd(PPh3)4(157mg，0.136mmol)，TEA(0.14g，1.34mmol)于100mL圆底烧瓶中，然后加DMF(5mL)溶解，混合物用氩气置换3次气体后置于110℃油浴中反应12小时。TLC监控反应终点(DCM/MeOH＝40/1)，反应约12小时后显示反应完毕。反应液用硅藻土抽滤，滤液旋干得粗品。粗品柱层析分离(DCM/MeOH＝40/1)黄色油状物320mg，收率：90％。[M+H]+523.22。
步骤7：化合物48-7的合成
称取48-6(320mg，0.612mmol)、K2OsO4·2H2O(22.5mg，0.0612mmol)、NMO(144mg，0.612mmol)于100mL圆底烧瓶中，然后加丙酮(3mL)和H2O(3mL)溶解，混合物在25℃反应12小时。TLC监控反应终点(DCM/MeOH＝20/1)， 反应约12小时后显示反应完毕。反应液用硅藻土抽滤，滤液旋干得粗品中间体([M+H]+557.29)。中间体溶于THF(2mL)和H2O(2mL)，然后加入NaIO4(132mg，0.619mmol)，混合物在25℃反应2小时。TLC监控反应终点(DCM/MeOH＝10/1)，反应约2小时后显示反应完毕。反应液加水淬灭，然后用DCM/MeOH＝20/1萃取，有机相旋干得粗品无色油状物147mg。[M+H]+525.24。
步骤8：化合物48-8的合成
称取48-7(20mg，0.038mmol)、NH2OH.HCl(11mg，0.152mmol)于100mL圆底烧瓶中，然后加EtOH(1mL)溶解，混合物在25℃反应12小时。TLC监控反应终点(DCM/MeOH＝20/1)，反应约12小时后显示反应完毕。反应液加水淬灭，然后用DCM进行萃取，有机相旋干得粗品。粗品柱层析分离(DCM/MeOH＝20/1)得黄色固体12mg，收率：60％。[M+H]+540.27。
步骤9：化合物48-9的合成
称取48-8(20mg，0.037mmol)于25mL圆底烧瓶中，加MeOH(3mL)和H2O(0.6mL)溶解，然后加入苯乙炔(6mg，0.0556mmol)、PhI(AcO)2(24mg，0.074mmol)，混合物在25℃反应12小时。TLC监控反应终点(DCM/MeOH＝40/1)，反应约12小时后显示反应完毕。反应液旋干得粗品。粗品柱层析分离(DCM/MeOH＝20/1)得无色油状物7mg，收率：30％。[M+H]+640.40。
步骤10：化合物48-10的合成
称取48-9(20mg，0.033mmol)于25mL圆底烧瓶中，加4M HCl/MeOH(1mL)溶解，混合物在25℃反应1小时。TLC监控反应终点(DCM/MeOH＝20/1)，反应约1小时后显示反应完毕。反应液加水淬灭，然后用DCM进行萃取，有机相旋干得粗品。粗品柱层析分离(DCM/MeOH＝25/1)得白色固体15mg,收率:79％。[M+H]+598.31。
步骤11：化合物48的合成
称取48-10(20mg，0.033mmol)于25mL圆底烧瓶中，加THF(1mL)溶解，然后加入LiAlH4(2.4mg，0.066mmol)，于25℃反应1小时。TLC监控反应终点(DCM/MeOH＝10/1)，反应约1小时后显示反应完毕。反应液旋干得粗品。粗品柱层析分离(DCM/MeOH＝10/1)得白色固体7mg，收率：58％。[M+H]+498.25。1H NMR(500MHz,DMSO-d6)δ7.95(d,J＝7.0Hz,2H),7.60–7.51(m,4H),7.08(d,J＝8.1Hz,1H),6.91(d,J＝2.1Hz,1H),6.71(dd,J＝8.1,2.4Hz,1H),5.24(t,J＝4.5Hz,1H),4.60(d,J＝4.1Hz,2H),3.86(dd,J＝15.6,11.9Hz,3H),3.73(s,3H),3.19–3.08(m,2H),2.98(d,J＝15.3Hz,1H),2.71(s,3H),2.55(d,J＝15.3Hz,1H),1.96–1.88(m,1H),1.79(td,J＝12.7,3.8Hz,1H),1.55(d,J＝12.5Hz,1H),1.15(d,J＝13.0Hz,1H)。
经由不同的起始原料和相应的试剂，采用与前述实施例48相似的方法合成得到下列目标物。
实施例56：化合物56的合成
称取48-4(56mg)、IM6(50mg)、Pd(pph3)4(25mg)、Na2CO3(22.3mg)于100mL圆底烧瓶中，加入DME/H2O(2/0.5mL)溶解。混合物用氩气置换3次气体后于100℃油浴中反应4小时。TLC监控反应(DCM/MeOH＝20/1)，显示反应完毕。反应液用甲醇稀释后，硅藻土抽滤，滤液旋干得粗品。粗品薄层制备分离(DCM/MeOH＝20/1)得白色固体21mg，收率：26％。[M+H]+622.28。
实施例57：化合物57的合成
称取化合物56(20mg)于100mL圆底烧瓶中，加THF(2mL)溶解，然后分批加入LiAlH4(20mg)。混合物在室温反应12小时。TLC监控反应(DCM/MeOH＝20/1)，显示反应完毕。反应液加饱和NH4Cl溶液淬灭，然后用(DCM/MeOH＝20/1)进行萃取，有机相旋干得粗品。粗品薄层制备分离(DCM/MeOH＝20/1)得白色固体7mg，收率：46％。[M+H]+580.26。
实施例58：SHP2酶活测试
为了测试化合物对SHP2-PTP酶活性的抑制作用，使用DiFMUP为替代底物的终点荧光酶法测定SHP2的催化活性，以确定化合物的IC50值。脱磷反应在黑色、384孔浅聚苯乙烯板上进行。总反应体积设为24μL/孔。为了使DMSO的浓度保持在较低的水平，将化合物从10mM开始用DMSO进行4倍梯度稀释，共计8个浓度。然后25倍稀释至反应缓冲液(60mM HEPES pH 7.2、75mM NaCl、75mM KCl、1mM EDTA、0.02％BSA、5mM DTT)，得到不同浓度的化合物溶液。0.5nM SHP2(购自美国Signalchem,p38-20G-10)与1μM p-IRS1肽(吉尔生化，86703)预孵育5到10分钟激活酶，然后加入不同浓度的化合物溶液或DMSO作为对照。在室温下反应30分钟，然后加入100μM DiFMUP(购自美国Invitrogen，D6567-5mg)底物，室温反应30分钟后，加入160μM的bpV(phen)(购自美国Sigma，SML0889-5mg)终止反应。反应结束后，将板子转移到Spectramax光谱仪上进行读板，激发波长为350nm，发射波长为450nm，通过监测反应产物DiFMUP在室温下积累的荧光信号变化来测定酶的催化速度。然后通过基于对照的归一化拟合来推断IC50值，绘制抑制剂剂量-反应曲线，数据如表4所示。结果显示本申请所涉及的化合物对SHP2酶活有很强的抑制效果。
表4

工业应用性
本发明提供一种SHP2抑制剂化合物，其可以用于抑制SHP2活性，并且/或者在受试者中治疗、预防或缓和由SHP2介导的疾病。因而，可将其制成相应的药物，适于工业应用。
尽管本文对本发明作了详细说明，但本发明不限于此，本技术领域的技术人员可以根据本发明的原理进行修改，因此，凡按照本发明的原理进行的各种修改都应当理解为落入本发明的保护范围。

Claims (26)

  1. 一种SHP2抑制剂，其为式I的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物：
    其中，
    A为芳基或杂芳基，优选地选自苯基、咪唑并吡啶基、噁二唑基、噁唑基和异噁唑基；
    B为含氮不饱和单环或双环，优选地选自吡嗪、吡唑并嘧啶酮、和吡唑并吡嗪；
    m和n各自独立地为0、1或2；
    R1和R1'各自独立地选自H、C1-6烷基、氨基、C1-6氨基烷基、羟基、C1-6羟基烷基、C1-6烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1至3个R6取代；
    R2和R2'各自为H，或连接在一起形成C2-4亚烷基；
    R3选自H、羟基、和卤素；
    R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C3-6环烷基C1-6烷基、C1-6羟基烷基、5或6元杂环烷基、5或6元杂环烷基C1-6烷基、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；
    R5各自独立地选自C1-C4烷基、C1-C4羟基烷基和C1-C4烷氧基羰基；
    R6各自独立地选自卤素、氨基和C1-6烷氧基。
  2. 如权利要求1所述的SHP2抑制剂，其中R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；更优选地，R1和R1'一起形成当存在R6时，R6选自卤素和C1-6烷氧基。
  3. 如权利要求1或2所述的SHP2抑制剂，其中A选自苯基、咪唑并[4,5-b]吡啶基、[1,2,4]噁二唑-3-基、和异噁唑-3-基；更优选地，A选自苯基、 且n为1或2。
  4. 如权利要求1或2所述的SHP2抑制剂，其中B选自且m为2、且m为1、和且m为0。
  5. 如权利要求1所述的SHP2抑制剂，其中
    R1和R1'各自独立地选自H、C1-3烷基、氨基、C1-3氨基烷基、羟基、C1-3羟基烷基、C1-3烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；
    R2和R2'各自为H，或连接在一起形成亚乙基；
    R3选自H、羟基、和氟；
    R4各自独立地选自卤素、C1-3烷基、C1-3卤代烷基、C3-5环烷基、C3-5环烷基C1-3烷基、C1-3羟基烷基、四氢呋喃基、四氢吡喃基、吗啉-4基乙基、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；
    R5各自独立地选自C1-C2烷基、C1-C2羟基烷基和C1-C2烷氧基羰基；
    R6各自独立地选自氟、氯、氨基和C1-3烷氧基。
  6. 如权利要求1或2所述的SHP2抑制剂，其中R2和R2'各自为H；R3为H；R6各自独立地选自卤素和C1-6烷氧基。
  7. 如权利要求1所述的SHP2抑制剂，其为式Ia的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物：
  8. 如权利要求7所述的SHP2抑制剂，其中
    A选自苯基、和咪唑并吡啶基、噁二唑基、噁唑基和异噁唑基；
    n为1或2；
    R1和R1'各自独立地选自C1-6烷基、C1-6氨基烷基、和羟基，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；
    R2和R2'各自为H，或连接在一起形成C2-4亚烷基；
    R3为H；
    R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C3-6环烷基C1-6烷基、苯基、和5或6元杂环烷基；
    R5为C1-C4烷基；
    R6选自卤素和C1-6烷氧基。
  9. 如权利要求7或8所述的SHP2抑制剂，其中A为咪唑并吡啶基，优选咪唑并[4,5-b]吡啶基，更优选地选自
  10. 如权利要求7或8所述的SHP2抑制剂，其中R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被卤素或C1-6烷氧基取代，更优选地被氟或甲氧基取代。
  11. 如权利要求1或7所述的SHP2抑制剂，其中所述化合物选自：

  12. 如权利要求1所述的SHP2抑制剂，其为式Ib的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物：
  13. 如权利要求12所述的SHP2抑制剂，其中
    A选自苯基、咪唑并吡啶基、噁二唑基、噁唑基和异噁唑基；
    n为1或2；
    R1和R1'各自独立地选自H、C1-6烷基、氨基、C1-6氨基烷基、羟基、C1-6羟基烷基、C1-6烷基酰胺基、和氧代，或者R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；
    R2和R2'各自为H，或连接在一起形成C2-4亚烷基；
    R3选自H、羟基、和卤素；
    R4各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C1-6羟基烷基、5或6元杂环烷基、5或6元杂环烷基C1-6烷基、和任选地被1至3个R6取代的苯基、吡啶基、嘧啶基、或异噁唑基；
    R6各自独立地选自卤素和C1-6烷氧基。
  14. 如权利要求12或13所述的SHP2抑制剂，其中A为咪唑并吡啶基，优选 咪唑并[4,5-b]吡啶基，更优选
  15. 如权利要求12或13所述的SHP2抑制剂，其中R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被C1-6烷氧基取代，更优选地被甲氧基取代。
  16. 如权利要求1或12所述的SHP2抑制剂，其中所述化合物选自：

  17. 如权利要求1所述的SHP2抑制剂，其为式Ic的化合物，或其药学上可接受的盐、异构体、溶剂化物、螯合物、多晶型物、酸、酯、代谢物或前体药物：
  18. 如权利要求17所述的SHP2抑制剂，其中
    A选自咪唑并吡啶基、噁二唑基、噁唑基和异噁唑基；
    n为1或2；
    R1和R1'一起形成苯并螺环戊基，其中戊基被氨基取代且苯基任选地被1个R6取代；
    R2和R2'各自为H；
    R3为H；
    R4各自独立地选自C1-6卤代烷基、C3-6环烷基、和任选地被1至3个R6取代的苯基、和吡啶基；
    R5选自C1-C4羟基烷基和C1-C4烷氧基羰基；
    R6各自独立地选自卤素、氨基和C1-6烷氧基。
  19. 如权利要求17或18所述的SHP2抑制剂，其中A为咪唑并吡啶基，优选咪唑并[4,5-b]吡啶基，更优选
  20. 如权利要求17或18所述的SHP2抑制剂，其中R5是C1-C4羟基烷基，优选羟甲基。
  21. 如权利要求1或17所述的SHP2抑制剂，其中所述化合物选自：

  22. 一种药物组合物，其包括根据权利要求1-21中任一项所述的SHP2抑制剂、和药学上可接受的稀释剂或载体、以及任选的其他活性药物成分。
  23. 根据权利要求1-21中任一项所述的SHP2抑制剂，用于抑制SHP2活性的用途。
  24. 根据权利要求1-21中任一项所述的SHP2抑制剂，用于治疗、预防或缓和由SHP2介导的疾病的用途。
  25. 如权利要求24所述的SHP2抑制剂的用途，其中所述疾病选自癌症、癌症转移、心血管疾病、免疫疾病、纤维化或眼部疾病。
  26. 如权利要求24或25所述的SHP2抑制剂的用途，其中所述疾病是选自青少年髓单核细胞白血病、神经母细胞瘤、黑色素瘤、头颈部鳞状细胞癌、急性髓性白血病、乳腺癌、食道肿瘤、肺癌、结肠癌、头癌、胃癌、淋巴瘤、胶质母细胞瘤、胰腺癌或其组合的癌症。
PCT/CN2023/089203 2022-05-20 2023-04-19 Shp2抑制剂及其用途 WO2023221721A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210550641 2022-05-20
CN202210550641.9 2022-05-20

Publications (1)

Publication Number Publication Date
WO2023221721A1 true WO2023221721A1 (zh) 2023-11-23

Family

ID=88774090

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/089203 WO2023221721A1 (zh) 2022-05-20 2023-04-19 Shp2抑制剂及其用途

Country Status (2)

Country Link
CN (1) CN117088887A (zh)
WO (1) WO2023221721A1 (zh)

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016203404A1 (en) * 2015-06-19 2016-12-22 Novartis Ag Compounds and compositions for inhibiting the activity of shp2
WO2017210134A1 (en) * 2016-05-31 2017-12-07 Board Of Regents, University Of Texas System Heterocyclic inhibitors of ptpn11
WO2018057884A1 (en) * 2016-09-22 2018-03-29 Relay Therapeutics, Inc. Shp2 phosphatase inhibitors and methods of use thereof
WO2019165073A1 (en) * 2018-02-21 2019-08-29 Relay Therapeutics, Inc. Shp2 phosphatase inhibitors and methods of use thereof
WO2019183364A1 (en) * 2018-03-21 2019-09-26 Relay Therapeutics, Inc. Pyrazolo[3,4-b]pyrazine shp2 phosphatase inhibitors and methods of use thereof
WO2019183367A1 (en) * 2018-03-21 2019-09-26 Relay Therapeutics, Inc. Shp2 phosphatase inhibitors and methods of use thereof
WO2019213318A1 (en) * 2018-05-02 2019-11-07 Board Of Regents, The University Of Texas System Substituted heterocyclic inhibitors of ptpn11
WO2020022323A1 (en) * 2018-07-24 2020-01-30 Taiho Pharmaceutical Co., Ltd. Heterobicyclic compounds for inhibiting the activity of shp2
WO2021142026A1 (en) * 2020-01-07 2021-07-15 Revolution Medicines, Inc. Shp2 inhibitor dosing and methods of treating cancer
WO2021197452A1 (zh) * 2020-04-03 2021-10-07 上海翰森生物医药科技有限公司 含氮杂芳类衍生物自由碱的晶型
WO2021218752A1 (en) * 2020-04-26 2021-11-04 Betta Pharmaceuticals Co., Ltd Shp2 inhibitors, compositions and uses thereof
WO2021249449A1 (en) * 2020-06-11 2021-12-16 Betta Pharmaceuticals Co., Ltd Shp2 inhibitors, compositions and uses thereof
CN114213417A (zh) * 2021-11-16 2022-03-22 郑州大学 吡唑并六元氮杂环类化合物及其合成方法和应用

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016203404A1 (en) * 2015-06-19 2016-12-22 Novartis Ag Compounds and compositions for inhibiting the activity of shp2
WO2017210134A1 (en) * 2016-05-31 2017-12-07 Board Of Regents, University Of Texas System Heterocyclic inhibitors of ptpn11
WO2018057884A1 (en) * 2016-09-22 2018-03-29 Relay Therapeutics, Inc. Shp2 phosphatase inhibitors and methods of use thereof
WO2019165073A1 (en) * 2018-02-21 2019-08-29 Relay Therapeutics, Inc. Shp2 phosphatase inhibitors and methods of use thereof
WO2019183364A1 (en) * 2018-03-21 2019-09-26 Relay Therapeutics, Inc. Pyrazolo[3,4-b]pyrazine shp2 phosphatase inhibitors and methods of use thereof
WO2019183367A1 (en) * 2018-03-21 2019-09-26 Relay Therapeutics, Inc. Shp2 phosphatase inhibitors and methods of use thereof
WO2019213318A1 (en) * 2018-05-02 2019-11-07 Board Of Regents, The University Of Texas System Substituted heterocyclic inhibitors of ptpn11
WO2020022323A1 (en) * 2018-07-24 2020-01-30 Taiho Pharmaceutical Co., Ltd. Heterobicyclic compounds for inhibiting the activity of shp2
WO2021142026A1 (en) * 2020-01-07 2021-07-15 Revolution Medicines, Inc. Shp2 inhibitor dosing and methods of treating cancer
WO2021197452A1 (zh) * 2020-04-03 2021-10-07 上海翰森生物医药科技有限公司 含氮杂芳类衍生物自由碱的晶型
WO2021218752A1 (en) * 2020-04-26 2021-11-04 Betta Pharmaceuticals Co., Ltd Shp2 inhibitors, compositions and uses thereof
WO2021249449A1 (en) * 2020-06-11 2021-12-16 Betta Pharmaceuticals Co., Ltd Shp2 inhibitors, compositions and uses thereof
CN114213417A (zh) * 2021-11-16 2022-03-22 郑州大学 吡唑并六元氮杂环类化合物及其合成方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CZAKO, B. ET AL.: "Discovery of 6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor", J. MED. CHEM., vol. 64, 13 October 2021 (2021-10-13), XP093006587, DOI: 10.1021/acs.jmedchem.1c01132 *

Also Published As

Publication number Publication date
CN117088887A (zh) 2023-11-21

Similar Documents

Publication Publication Date Title
WO2019196812A1 (zh) 蛋白降解靶向化合物、其抗肿瘤应用、其中间体及中间体应用
WO2019158019A1 (zh) 嘧啶并环化合物及其制备方法和应用
WO2020094104A1 (zh) 一类含氮稠杂环类shp2抑制剂化合物、制备方法和用途
TW202043212A (zh) Shp2抑制劑及其應用
CN102093364B (zh) 作为FAK/Pyk2抑制剂的2,4-二氨基-6,7-二氢-5H-吡咯并[2,3]嘧啶衍生物
CN111440189B (zh) 稠环嘧啶氨基衍生物、其制备方法、中间体、药物组合物及应用
CN106749233B (zh) 一类磺酰胺衍生物及其应用
WO2018045956A1 (zh) 苯并咪唑类化合物激酶抑制剂及其制备方法和应用
TWI781938B (zh) 苯基丙醯胺類衍生物、其製備方法及其在醫藥上的應用
WO2019020070A1 (zh) 哌嗪并杂芳基类衍生物、其制备方法及其在医药上的应用
WO2019134539A1 (zh) 二氢吡唑酮并嘧啶类化合物及其制备方法和用途
WO2016169421A1 (zh) 咪唑并异吲哚类衍生物、其制备方法及其在医药上的应用
BR112013025732B1 (pt) Compostos de imizazo-oxazina, seus usos e composição farmacêutica e fármaco compreendendo os mesmos
WO2020007322A1 (zh) 一种靶向降解bet蛋白的化合物及其应用
EP3426244B1 (en) 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
EP3496724B1 (en) Protein kinase regulators
CN103476776A (zh) 作为FAK/Pyk2抑制剂的2,4-二氨基-6,7-二氢-5H-吡咯并[2,3]嘧啶衍生物
CN107108586A (zh) 多环类间变性淋巴瘤激酶抑制剂
WO2020156479A1 (zh) 环丙烯并苯并呋喃取代的氮杂芳基化合物、其中间体、制备方法及应用
WO2022135590A1 (zh) 一类嘧啶并杂环类化合物、制备方法和用途
WO2022268230A1 (zh) 作为kif18a抑制剂的化合物
WO2022089389A1 (zh) 杂环化合物及其制备方法、药物组合物和应用
WO2022105921A1 (zh) 一类嘧啶并杂环类化合物、制备方法和用途
WO2015189433A1 (en) Pyridazinones for the treatment of cancer
CN110392681B (zh) 基于甲苯磺酰基乙酸酯的化合物及其衍生物作为phgdh抑制剂

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23806674

Country of ref document: EP

Kind code of ref document: A1